Is ABCA4 p.Trp439Ter (c.1317G>A) pathogenic?

ABCA4 p.Trp439Ter (c.1317G>A) is classified Pathogenic in ABCA4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-19). Very rare (popmax 0.00313%, afr); Associated with ABCA4-related disorder.

What condition is associated with ABCA4 p.Trp439Ter (c.1317G>A)?

ABCA4 p.Trp439Ter (c.1317G>A) is associated with ABCA4-related disorder, retinal disorder (ClinVar).

How common is ABCA4 p.Trp439Ter (c.1317G>A) in the general population?

ABCA4 p.Trp439Ter (c.1317G>A) is very rare (popmax 0.00313%, afr) (gnomAD).

ABCA4 p.Trp439Ter

c.1317G>A · rs61752391 · VCV99043

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00313%, afr)

Conditions

ABCA4-related disorder

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.1317G>A; p.Trp439Ter variant in ABCA4 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 10 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 0.00002601 (37/1422478 alleles), which is lower than the ClinGen ABCA4 VCEP’s threshold (<0.0001) for PM2_Supporting. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls with an OR of 101.5 and CI of 24.08 to 923.23, 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 10 of 50
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.8, phastCons 1
Overall
CADD	39.0	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 0.00313% African / African-American · 2/63,988 alleles

Filtering AF 0.00221% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00194%

Overall 0.0026% 37/1,422,478 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00394%	25,400
African / African-Americangrpmax	0.00313%	31,994
European (non-Finnish)	0.00309%	32,327

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Trp439Ter
Coding: c.1317G>A
MANE Select: NM_000350
dbSNP: rs61752391
Type: single nucleotide variant
Location: chr1:94078629 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 439: 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); an α-helix; a disulfide bond

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

Disease context

Also linked: retinal disorder

Similar variants

ABCA4 p.Trp439Cys Uncertain significance ★★ ⚠ same residue
ABCA4 c.5196+1137G>A Pathogenic ★★★ same condition
ABCA4 c.5461-10T>C Pathogenic ★★★ same condition
ABCA4 c.5714+5G>A Pathogenic ★★★ same condition
ABCA4 p.Arg1108Cys Pathogenic ★★★ ⚠ same condition
ABCA4 p.Arg2030Gln Pathogenic ★★★ ⚠ same condition
ABCA4 p.Arg212Cys Pathogenic ★★★ ⚠ same condition
ABCA4 p.Arg572Gln 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-trp439ter (accessed [today's date]).

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