Is ALMS1 p.Pro253= (c.759T>A) pathogenic?

ALMS1 p.Pro253= (c.759T>A) is classified Conflicting classifications of pathogenicity in ALMS1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-24). Ultra-rare (popmax 0.0669%, afr); Associated with Alstrom syndrome.

What condition is associated with ALMS1 p.Pro253= (c.759T>A)?

ALMS1 p.Pro253= (c.759T>A) is associated with Alstrom syndrome (ClinVar).

How common is ALMS1 p.Pro253= (c.759T>A) in the general population?

ALMS1 p.Pro253= (c.759T>A) is ultra-rare (popmax 0.0669%, afr) (gnomAD).

How is Alström syndrome inherited?

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

ALMS1 p.Pro253=

c.759T>A · rs201478438 · VCV391952

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0669%, afr)

Conditions

Alstrom syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 2.1, phastCons 1
Overall
CADD	11.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0669% African / African-American · 50/74,780 alleles

Filtering AF 0.0521% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0468%

Overall 0.0033% 53/1,604,122 alleles · ultra-rare exomes 25/1,451,830 · genomes 28/152,292 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0669%	1,496
Admixed American	0.005%	19,991

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.Pro253=
Coding: c.759T>A
MANE Select: NM_001378454
dbSNP: rs201478438
Type: single nucleotide variant
Location: chr2:73422969 (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

Alstrom syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Alström syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

ALMS1 p.Pro253Ser Uncertain significance ★★ ⚠ 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-pro253 (accessed [today's date]).

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