Is ALMS1 p.Thr1663Ile (c.4988C>T) pathogenic?

ALMS1 p.Thr1663Ile (c.4988C>T) is classified Conflicting classifications of pathogenicity in ALMS1 (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-01-29). AlphaMissense: likely benign (0.106); Rare (popmax 0.916%, afr); Associated with monogenic diabetes.

What condition is associated with ALMS1 p.Thr1663Ile (c.4988C>T)?

ALMS1 p.Thr1663Ile (c.4988C>T) is associated with monogenic diabetes, Alstrom syndrome (ClinVar).

How common is ALMS1 p.Thr1663Ile (c.4988C>T) in the general population?

ALMS1 p.Thr1663Ile (c.4988C>T) is rare (popmax 0.916%, afr) (gnomAD).

What do computational predictors say about ALMS1 p.Thr1663Ile (c.4988C>T)?

AlphaMissense predicts likely benign (score 0.106) — an in-silico prediction, not a clinical call.

ALMS1 p.Thr1663Ile

c.4988C>T · rs188807564 · VCV241000

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.106 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.916%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

monogenic diabetes

Computational evidence

Protein change
AlphaMissense	0.106	likely benign
REVEL	0.008	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	0.005	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 0.916% African / African-American · 686/74,910 alleles

Filtering AF 0.859% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.836%

Overall 0.046% 743/1,613,754 alleles · rare exomes 362/1,461,824 · genomes 381/151,930 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.916%	109
Remaining individualsnot grpmax-eligible	0.0496%	2,016
Admixed American	0.03%	3,333
Middle Eastern	0.0165%	6,060
European (non-Finnish)	0.000593%	168,556

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.Thr1663Ile
Coding: c.4988C>T
MANE Select: NM_001378454
dbSNP: rs188807564
Type: single nucleotide variant
Location: chr2:73451515 (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

monogenic diabetes — 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.Thr1663Ala 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-thr1663ile (accessed [today's date]).

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