Is ABCA4 p.Pro2103His (c.6308C>A) pathogenic?

ABCA4 p.Pro2103His (c.6308C>A) is classified Conflicting classifications of pathogenicity in ABCA4 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2022-09-05). AlphaMissense: likely pathogenic (0.8878); Absent from gnomAD v4.1; Associated with severe early-childhood-onset retinal dystrophy.

What condition is associated with ABCA4 p.Pro2103His (c.6308C>A)?

ABCA4 p.Pro2103His (c.6308C>A) is associated with severe early-childhood-onset retinal dystrophy, Stargardt disease (ClinVar).

How common is ABCA4 p.Pro2103His (c.6308C>A) in the general population?

ABCA4 p.Pro2103His (c.6308C>A) is absent from gnomAD v4.1 (gnomAD).

How is Severe early-childhood-onset retinal dystrophy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCA4 p.Pro2103His (c.6308C>A)?

AlphaMissense predicts likely pathogenic (score 0.8878) — an in-silico prediction, not a clinical call.

ABCA4 p.Pro2103His

c.6308C>A · rs2100994049 · VCV1172702

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8878 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

severe early-childhood-onset retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.8878	likely pathogenic · top 10% in ABCA4
REVEL	0.946	strongly pathogenic-leaning
SaProt	LLR -15.46	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ABCA4
Protein: p.Pro2103His
Coding: c.6308C>A
MANE Select: NM_000350
dbSNP: rs2100994049
Type: single nucleotide variant
Location: chr1:94001080 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 2103: 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); an α-helix

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

Disease context

severe early-childhood-onset retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Stargardt disease

For Severe early-childhood-onset retinal dystrophy (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

ABCA4 c.1937+1G>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
ABCA4 c.4773+3A>G Pathogenic ★★★ same condition
ABCA4 c.5018+2T>C Pathogenic ★★★ same condition
ABCA4 c.5196+1137G>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-pro2103his (accessed [today's date]).

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