Is ALMS1 p.Thr1663Pro (c.4987A>C) pathogenic?

ALMS1 p.Thr1663Pro (c.4987A>C) is classified Uncertain significance in ALMS1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-09). AlphaMissense: likely benign (0.0768); Very rare (popmax 0.000339%, nfe); Associated with Alstrom syndrome.

What condition is associated with ALMS1 p.Thr1663Pro (c.4987A>C)?

ALMS1 p.Thr1663Pro (c.4987A>C) is associated with Alstrom syndrome (ClinVar).

How common is ALMS1 p.Thr1663Pro (c.4987A>C) in the general population?

ALMS1 p.Thr1663Pro (c.4987A>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

How is Alström syndrome inherited?

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

What do computational predictors say about ALMS1 p.Thr1663Pro (c.4987A>C)?

AlphaMissense predicts likely benign (score 0.0768) — an in-silico prediction, not a clinical call.

ALMS1 p.Thr1663Pro

c.4987A>C · rs770424780 · VCV1744597

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0768 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Alstrom syndrome

Computational evidence

Protein change
AlphaMissense	0.0768	likely benign
REVEL	0.015	strongly 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 -20	GERP -4.1
Regional constraint	o/e 1.12	unconstrained · MANE · 224 kb · p 1.9e-16 · regional, not allelic
Overall
CADD	0.002	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 0.000339% European (non-Finnish) · 4/1,179,922 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,672 alleles · very rare exomes 2/1,461,828 · genomes 2/151,844 · joint denominator

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.Thr1663Pro
Coding: c.4987A>C
MANE Select: NM_001378454
dbSNP: rs770424780
Type: single nucleotide variant
Location: chr2:73451514 (GRCh38)
Gene constraint: LOEUF 0.825 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1663: 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.Thr1663Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
ALMS1 p.Thr1663Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
ALMS1 p.Thr1663= 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

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-thr1663pro (accessed [today's date]).

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