Is ALMS1 p.Pro9Ser (c.25C>T) pathogenic?

ALMS1 p.Pro9Ser (c.25C>T) is classified Uncertain significance in ALMS1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-07-08). AlphaMissense: likely pathogenic (0.8549); Ultra-rare (popmax 0.0504%, sas); Associated with Cardiovascular phenotype.

What condition is associated with ALMS1 p.Pro9Ser (c.25C>T)?

ALMS1 p.Pro9Ser (c.25C>T) is associated with Cardiovascular phenotype, Alstrom syndrome (ClinVar).

How common is ALMS1 p.Pro9Ser (c.25C>T) in the general population?

ALMS1 p.Pro9Ser (c.25C>T) is ultra-rare (popmax 0.0504%, sas) (gnomAD).

What do computational predictors say about ALMS1 p.Pro9Ser (c.25C>T)?

AlphaMissense predicts likely pathogenic (score 0.8549) — an in-silico prediction, not a clinical call.

ALMS1 p.Pro9Ser

c.25C>T · rs769538172 · VCV641250

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8549 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0504%, sas)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.8549	likely pathogenic · top 2% in ALMS1
REVEL	0.091	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 224 kb · p 1.9e-16 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0504% South Asian · 35/69,498 alleles

Filtering AF 0.0371% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0326%

Overall 0.00542% 47/867,892 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0504%	1,986
Remaining individualsnot grpmax-eligible	0.0106%	9,444
Admixed American	0.00406%	24,626
European (non-Finnish)	0.00112%	89,574

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.Pro9Ser
Coding: c.25C>T
MANE Select: NM_001378454
dbSNP: rs769538172
Type: single nucleotide variant
Location: chr2:73385893 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 9: the 'disordered' region

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.Pro9Leu Uncertain significance ★★ ⚠ same residue
ALMS1 p.Pro9= 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

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-pro9ser (accessed [today's date]).

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