Is ABCA4 p.Pro62Leu (c.185C>T) pathogenic?

ABCA4 p.Pro62Leu (c.185C>T) is classified Conflicting classifications of pathogenicity in ABCA4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-27). AlphaMissense: likely pathogenic (0.6917); Very rare (popmax 8.47e-05%, nfe); Associated with ABCA4-related disorder.

What condition is associated with ABCA4 p.Pro62Leu (c.185C>T)?

ABCA4 p.Pro62Leu (c.185C>T) is associated with ABCA4-related disorder (ClinVar).

How common is ABCA4 p.Pro62Leu (c.185C>T) in the general population?

ABCA4 p.Pro62Leu (c.185C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ABCA4 p.Pro62Leu (c.185C>T)?

AlphaMissense predicts likely pathogenic (score 0.6917) — an in-silico prediction, not a clinical call.

ABCA4 p.Pro62Leu

c.185C>T · rs1057520211 · VCV377400

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6917 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCA4-related disorder

Computational evidence

Protein change
AlphaMissense	0.6917	likely pathogenic
REVEL	0.945	strongly pathogenic-leaning
SaProt	LLR -9.85	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	28.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,044 alleles

Overall 0.000137% 2/1,461,890 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)grpmax	8.47e-05%	1,180,044

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.Pro62Leu
Coding: c.185C>T
MANE Select: NM_000350
dbSNP: rs1057520211
Type: single nucleotide variant
Location: chr1:94111555 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 62: an α-helix; a disulfide bond; a UniProt-annotated variant site (in stgd1; uncertain significance); a UniProt-annotated variant site (in cord3; uncertain significance)

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

Disease context

ABCA4-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCA4 p.Pro62Ala Pathogenic/Likely pathogenic ★★ same residue
ABCA4 p.Pro62Ser Likely pathogenic ★★ same residue
ABCA4 p.Pro62Thr Likely pathogenic ★ same residue
ABCA4 p.Pro62= Likely benign ★ same residue
ABCA4 c.1099+2T>G Pathogenic/Likely pathogenic ★★ same condition
ABCA4 c.160+5G>C Pathogenic/Likely pathogenic ★★ same condition
ABCA4 c.1937+1G>C Pathogenic/Likely pathogenic ★★ same condition
ABCA4 c.1938-619A>G Pathogenic/Likely 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-pro62leu (accessed [today's date]).

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