Is ABCA4 p.Arg681Ter (c.2041C>T) pathogenic?

ABCA4 p.Arg681Ter (c.2041C>T) is classified Pathogenic in ABCA4 (ClinVar, Expert panel, 20 submitters; last evaluated 2026-07-28). Very rare (popmax 0.00223%, eas); Associated with ABCA4-related retinopathy.

What condition is associated with ABCA4 p.Arg681Ter (c.2041C>T)?

ABCA4 p.Arg681Ter (c.2041C>T) is associated with ABCA4-related retinopathy, age related macular degeneration 2, benign concentric annular macular dystrophy (ClinVar).

How common is ABCA4 p.Arg681Ter (c.2041C>T) in the general population?

ABCA4 p.Arg681Ter (c.2041C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

ABCA4 p.Arg681Ter

c.2041C>T · rs61749423 · VCV99114

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 20 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

ABCA4-related retinopathy

ClinGen expert panel — ABCA4 VCEP

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

PVS1 PM2_Supporting PS4

Curation rationale (ClinGen, verbatim)

The NM_000350.3(ABCA4):c.2041C>T, p.Arg681Ter variant in ABCA4 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 14 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 v4.1.1 is 0.00001921 (31/1613940 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 an OR of 667.8 and CI of 115.11 to 16384.00, which is above the ABCA4 VCEP threshold of ≥5, where the CI does not contain 1 (PS4; PMID: 35120629). 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 (Specification Version 1): PVS1, PS4, 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 14 of 50
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -2, phastCons 1
Overall
CADD	36.0	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 0.00223% East Asian · 1/44,888 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00192% 31/1,613,940 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,888
European (non-Finnish)	0.0022%	45,385
South Asian	0.0022%	45,533
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00134%	74,884

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.Arg681Ter
Coding: c.2041C>T
MANE Select: NM_000350
dbSNP: rs61749423
Type: single nucleotide variant
Location: chr1:94060656 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 681: 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); a disulfide bond

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

Disease context

Also linked: age related macular degeneration 2 benign concentric annular macular dystrophy severe early-childhood-onset retinal dystrophy Stargardt disease 3 retinitis pigmentosa 19 cone-rod dystrophy 3 Leber congenital amaurosis inherited retinal dystrophy

Similar variants

ABCA4 p.Arg681Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCA4 p.Arg681= Likely benign ★ 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
ABCA4 c.4352+1G>A 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-arg681ter (accessed [today's date]).

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