Is ABCA4 p.Arg2149Ter (c.6445C>T) pathogenic?

ABCA4 p.Arg2149Ter (c.6445C>T) is classified Pathogenic in ABCA4 (ClinVar, Expert panel, 14 submitters; last evaluated 2025-12-05). Very rare (popmax 0.00891%, eas); Associated with ABCA4-related retinopathy.

What condition is associated with ABCA4 p.Arg2149Ter (c.6445C>T)?

ABCA4 p.Arg2149Ter (c.6445C>T) is associated with ABCA4-related retinopathy, blindness (disorder), macular degeneration (ClinVar).

How common is ABCA4 p.Arg2149Ter (c.6445C>T) in the general population?

ABCA4 p.Arg2149Ter (c.6445C>T) is very rare (popmax 0.00891%, eas) (gnomAD).

ABCA4 p.Arg2149Ter

c.6445C>T · rs61750654 · VCV99460

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 14 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Conditions

ABCA4-related retinopathy

ClinGen expert panel — ABCA4 VCEP

Pathogenic for ABCA4-related retinopathy. Applied ACMG criteria (verbatim):

PVS1 PM3_Supporting PM2_Supporting PS4

Curation rationale (ClinGen, verbatim)

The NM_000350.3:c.6445C>T (p.Arg2149Ter) variant in ABCA4 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 47 out of 50 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The total minor allele frequency in gnomAD v4.1.0 is 0.000006196 (10/1614050 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold for PM2_Supporting (<0.0001). The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls with and OR of 86.3 and the CI is 30.40-338.60, which is above the ABCA4 VCEP threshold of >5, where the CI does not contain 1 (PS4; PMID: 35120629). This variant has been detected in at least 1 individual who was homozygous for the variant (PMID: 36284460; PM3_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for ABCA4-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP: PVS1, PS4, PM3_Supporting, PM2_Supporting.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 47 of 50
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.29	loss · gain 0.04 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 8.5	GERP -0.45, phastCons 1
Overall
CADD	54.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,890 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00062% 10/1,614,050 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,223
African / African-American	0.00133%	74,918
South Asian	0.0011%	91,084
European (non-Finnish)	0.000339%	295,010

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ABCA4
Protein: p.Arg2149Ter
Coding: c.6445C>T
MANE Select: NM_000350
dbSNP: rs61750654
Type: single nucleotide variant
Location: chr1:94000870 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 2149: a UniProt-annotated variant site (in cord3; uncertain significance); a UniProt-annotated variant site (in stgd1; uncertain significance); a UniProt-annotated variant site (found in a patient with chorioretinal atrophy; uncertain significance); a UniProt-annotated variant site (found in a patient with macular dystrophy; uncertain significance); the abc transporter 2 domain; a UniProt-annotated variant site (in stgd1 and cord3; uncertain significance); a UniProt-annotated variant site (sequence variant); a UniProt-annotated variant site (in stgd1 and ffm; uncertain significance); a UniProt-annotated variant site (in stgd1; uncertain significance; also found in a patient with chorioretinal atrophy; uncertain significance); a UniProt-annotated variant site (in stgd1); a β-strand

Full ABCA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: blindness (disorder)macular degeneration severe early-childhood-onset retinal dystrophy retinitis pigmentosa 19 inherited retinal dystrophy

Similar variants

ABCA4 p.Arg2149Gln Uncertain significance ★★ ⚠ same residue
ABCA4 p.Arg2149Leu Likely pathogenic ★ ⚠ same residue
ABCA4 p.Arg2149Pro Conflicting classifications of pathogenicity ★ same residue
ABCA4 c.1937+1G>A Pathogenic ★★★ same condition
ABCA4 c.3328+2T>A Pathogenic ★★★ same condition
ABCA4 c.3523-1G>A Pathogenic ★★★ same condition
ABCA4 c.4253+43G>A Pathogenic ★★★ same condition
ABCA4 c.4254-1G>C Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/abca4-p-arg2149ter (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown