Is ABCA4 p.Pro2174Leu (c.6521C>T) pathogenic?

ABCA4 p.Pro2174Leu (c.6521C>T) is classified Uncertain significance in ABCA4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-02). AlphaMissense: likely benign (0.0883); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with ABCA4 p.Pro2174Leu (c.6521C>T)?

ABCA4 p.Pro2174Leu (c.6521C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ABCA4 p.Pro2174Leu (c.6521C>T) in the general population?

ABCA4 p.Pro2174Leu (c.6521C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ABCA4 p.Pro2174Leu (c.6521C>T)?

AlphaMissense predicts likely benign (score 0.0883) — an in-silico prediction, not a clinical call.

ABCA4 p.Pro2174Leu

c.6521C>T · rs756641536 · VCV961435

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0883 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0883	likely benign
REVEL	0.659	pathogenic-leaning
SaProt	LLR -7.41	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.56, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 128 kb · p 0.24 · regional, not allelic
Overall
CADD	22.6	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 0.00167% Admixed American · 1/60,026 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000821% 12/1,461,870 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,026
South Asian	0.0011%	91,072
European (non-Finnish)	0.000847%	118,003

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.Pro2174Leu
Coding: c.6521C>T
MANE Select: NM_000350
dbSNP: rs756641536
Type: single nucleotide variant
Location: chr1:93998069 (GRCh38)
Gene constraint: LOEUF 0.786 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.96 · 8 PDB
Residue 2174: 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 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)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCA4 p.Pro2174= Likely benign ★★ same residue
ABCA4 p.Ala1287Val Uncertain significance ★★ ⚠ same condition
ABCA4 p.Ala1324Val Uncertain significance ★★ ⚠ same condition
ABCA4 p.Ala45Gly Uncertain significance ★★ ⚠ same condition
ABCA4 p.Arg1170Thr Uncertain significance ★★ ⚠ same condition
ABCA4 p.Arg140Pro Uncertain significance ★★ ⚠ same condition
ABCA4 p.Arg1963His Uncertain significance ★★ ⚠ same condition
ABCA4 p.Arg487Pro Uncertain significance ★★ ⚠ 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-pro2174leu (accessed [today's date]).

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