Is ALMS1 p.Thr1663Ala (c.4987A>G) pathogenic?

ALMS1 p.Thr1663Ala (c.4987A>G) is classified Conflicting classifications of pathogenicity in ALMS1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-21). AlphaMissense: likely benign (0.0759); Very rare (popmax 0.00848%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with ALMS1 p.Thr1663Ala (c.4987A>G)?

ALMS1 p.Thr1663Ala (c.4987A>G) is associated with Cardiovascular phenotype, Alstrom syndrome (ClinVar).

How common is ALMS1 p.Thr1663Ala (c.4987A>G) in the general population?

ALMS1 p.Thr1663Ala (c.4987A>G) is very rare (popmax 0.00848%, nfe) (gnomAD).

What do computational predictors say about ALMS1 p.Thr1663Ala (c.4987A>G)?

AlphaMissense predicts likely benign (score 0.0759) — an in-silico prediction, not a clinical call.

ALMS1 p.Thr1663Ala

c.4987A>G · rs770424780 · VCV1206294

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0759 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00848%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0759	likely benign
REVEL	0.013	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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00848% European (non-Finnish) · 100/1,179,922 alleles

Filtering AF 0.00708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0066%

Overall 0.00638% 103/1,613,672 alleles · very rare exomes 98/1,461,828 · genomes 5/151,844 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00848%	11,799
Remaining individualsnot grpmax-eligible	0.0032%	31,242
Admixed American	0.00167%	59,970

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.Thr1663Ala
Coding: c.4987A>G
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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Alstrom syndrome

Similar variants

ALMS1 p.Thr1663Pro Uncertain significance ★★ ⚠ 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-thr1663ala (accessed [today's date]).

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