Is ALMS1 p.Pro3990Ala (c.11968C>G) pathogenic?

ALMS1 p.Pro3990Ala (c.11968C>G) is classified Uncertain significance in ALMS1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-04-21). AlphaMissense: likely benign (0.1555); Ultra-rare (popmax 0.0566%, amr); Associated with Cardiovascular phenotype.

What condition is associated with ALMS1 p.Pro3990Ala (c.11968C>G)?

ALMS1 p.Pro3990Ala (c.11968C>G) is associated with Cardiovascular phenotype, Alstrom syndrome (ClinVar).

How common is ALMS1 p.Pro3990Ala (c.11968C>G) in the general population?

ALMS1 p.Pro3990Ala (c.11968C>G) is ultra-rare (popmax 0.0566%, amr) (gnomAD).

What do computational predictors say about ALMS1 p.Pro3990Ala (c.11968C>G)?

AlphaMissense predicts likely benign (score 0.1555) — an in-silico prediction, not a clinical call.

ALMS1 p.Pro3990Ala

c.11968C>G · rs189851617 · VCV1435595

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1555 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0566%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1555	likely benign
REVEL	0.227	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP 1, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 224 kb · p 1.9e-16 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0566% Admixed American · 34/60,024 alleles

Filtering AF 0.0416% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0365%

Overall 0.00527% 85/1,614,176 alleles · ultra-rare exomes 74/1,461,886 · genomes 11/152,290 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0566%	1,765
Remaining individualsnot grpmax-eligible	0.0096%	10,418
European (non-Finnish)	0.00381%	26,223

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.Pro3990Ala
Coding: c.11968C>G
MANE Select: NM_001378454
dbSNP: rs189851617
Type: single nucleotide variant
Location: chr2:73601290 (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 p.Pro3990= Likely benign ★ same residue
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

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-pro3990ala (accessed [today's date]).

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