Is ALMS1 p.Pro2004fs (c.6006_6009dup) pathogenic?

ALMS1 p.Pro2004fs (c.60066009dup) is classified Likely pathogenic in ALMS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-10). Very rare (popmax 0.000763%, nfe); Associated with Alstrom syndrome.

What condition is associated with ALMS1 p.Pro2004fs (c.6006_6009dup)?

ALMS1 p.Pro2004fs (c.6006_6009dup) is associated with Alstrom syndrome (ClinVar).

How common is ALMS1 p.Pro2004fs (c.6006_6009dup) in the general population?

ALMS1 p.Pro2004fs (c.6006_6009dup) is very rare (popmax 0.000763%, nfe) (gnomAD).

How is Alström syndrome inherited?

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

ALMS1 p.Pro2004fs

c.6006_6009dup · VCV4815796

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

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 8 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.55	GERP -3.3
Overall
CADD	17.03	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 0.000763% European (non-Finnish) · 9/1,179,934 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,613,856 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.Pro2004fs
Coding: c.6006_6009dup
MANE Select: NM_001378454
Type: Microsatellite
Location: chr2:73452531 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2004: the '34 x 47 aa approximate tandem repeat' region

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.Arg2319fs Pathogenic/Likely pathogenic ★★ same condition
ALMS1 p.Arg3610fs Pathogenic ★★ same condition
ALMS1 p.Arg3817fs Pathogenic ★★ same condition
ALMS1 p.Asn1638fs Pathogenic ★★ same condition
ALMS1 p.Cys3052fs Pathogenic/Likely pathogenic ★★ same condition
ALMS1 p.Cys336_Asp337delinsTer Pathogenic ★★ same condition
ALMS1 p.Glu2434fs Pathogenic ★★ same condition
ALMS1 p.Glu3524fs 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-pro2004fs (accessed [today's date]).

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