Is ALMS1 p.Pro3130fs (c.9386dup) pathogenic?

ALMS1 p.Pro3130fs (c.9386dup) is classified Pathogenic/Likely pathogenic in ALMS1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-10). Very rare (popmax 0.00801%, afr); Associated with Alstrom syndrome.

What condition is associated with ALMS1 p.Pro3130fs (c.9386dup)?

ALMS1 p.Pro3130fs (c.9386dup) is associated with Alstrom syndrome (ClinVar).

How common is ALMS1 p.Pro3130fs (c.9386dup) in the general population?

ALMS1 p.Pro3130fs (c.9386dup) is very rare (popmax 0.00801%, afr) (gnomAD).

How is Alström syndrome inherited?

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

ALMS1 p.Pro3130fs

c.9386dup · rs1361923069 · VCV2691461

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Conditions

Alstrom syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.4	GERP 0.91, phastCons 1
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00801% African / African-American · 6/74,922 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000372% 6/1,614,062 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.Pro3130fs
Coding: c.9386dup
MANE Select: NM_001378454
dbSNP: rs1361923069
Type: Duplication
Location: chr2:73491344 (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.Pro3130Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
ALMS1 p.Pro3130Leu Uncertain significance ★ ⚠ same residue
ALMS1 p.Arg1006fs Pathogenic ★★ same condition
ALMS1 p.Gln1724fs Pathogenic/Likely pathogenic ★★ same condition
ALMS1 p.Gln3378fs Pathogenic ★★ same condition
ALMS1 p.Gln95fs Pathogenic/Likely pathogenic ★★ same condition
ALMS1 p.Glu1450Ter Pathogenic/Likely pathogenic ★★ same condition
ALMS1 p.Leu1726fs 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-pro3130fs (accessed [today's date]).

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