Is ALMS1 p.Ala2256Pro (c.6766G>C) pathogenic?

ALMS1 p.Ala2256Pro (c.6766G>C) is classified Conflicting classifications of pathogenicity in ALMS1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-12). AlphaMissense: likely benign (0.1618); Very rare (popmax 0.000169%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with ALMS1 p.Ala2256Pro (c.6766G>C)?

ALMS1 p.Ala2256Pro (c.6766G>C) is associated with Cardiovascular phenotype, Alstrom syndrome (ClinVar).

How common is ALMS1 p.Ala2256Pro (c.6766G>C) in the general population?

ALMS1 p.Ala2256Pro (c.6766G>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ALMS1 p.Ala2256Pro (c.6766G>C)?

AlphaMissense predicts likely benign (score 0.1618) — an in-silico prediction, not a clinical call.

ALMS1 p.Ala2256Pro

c.6766G>C · rs904787531 · VCV2085182

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1618 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1618	likely benign
REVEL	0.028	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -0.6, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 224 kb · p 1.9e-16 · regional, not allelic
Overall
CADD	19.93	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 0.000169% European (non-Finnish) · 2/1,179,978 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,734 alleles · very rare

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: ALMS1
Protein: p.Ala2256Pro
Coding: c.6766G>C
MANE Select: NM_001378454
dbSNP: rs904787531
Type: single nucleotide variant
Location: chr2:73453293 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

Full ALMS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Alstrom syndrome

Similar variants

ALMS1 c.10079-1G>C Likely pathogenic ★★ same condition
ALMS1 c.10214-2A>G Likely pathogenic ★★ same condition
ALMS1 c.10384+1G>A Likely pathogenic ★★ same condition
ALMS1 c.10385-2A>G Pathogenic ★★ same condition
ALMS1 c.11547+3A>T Likely pathogenic ★★ same condition
ALMS1 c.11668+1G>T Pathogenic/Likely pathogenic ★★ same condition
ALMS1 c.11669-1G>A Pathogenic ★★ same condition
ALMS1 c.11669-1G>C 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/alms1-p-ala2256pro (accessed [today's date]).

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