Is HTT p.Ala1664Val (c.4991C>T) pathogenic?

HTT p.Ala1664Val (c.4991C>T) is classified Uncertain significance in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-17). AlphaMissense: likely benign (0.1009); Ultra-rare (popmax 0.0379%, eas).

How common is HTT p.Ala1664Val (c.4991C>T) in the general population?

HTT p.Ala1664Val (c.4991C>T) is ultra-rare (popmax 0.0379%, eas) (gnomAD).

What do computational predictors say about HTT p.Ala1664Val (c.4991C>T)?

AlphaMissense predicts likely benign (score 0.1009) — an in-silico prediction, not a clinical call.

HTT p.Ala1664Val

c.4991C>T · rs368118407 · VCV1474095

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1009 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1009	likely benign
REVEL	0.151	moderately 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 2.6	GERP 2.1, phastCons 0.99
Overall
CADD	22.7	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 0.0379% East Asian · 17/44,850 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.0023% 37/1,608,732 alleles · ultra-rare exomes 31/1,456,508 · genomes 6/152,224 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0379%	2,638
South Asian	0.0143%	6,972
African / African-American	0.00534%	18,711
Admixed American	0.00167%	59,848
Remaining individualsnot grpmax-eligible	0.0016%	62,318
European (non-Finnish)	8.51e-05%	1,175,718

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: HTT
Protein: p.Ala1664Val
Coding: c.4991C>T
MANE Select: NM_001388492
dbSNP: rs368118407
Type: single nucleotide variant
Location: chr4:3187652 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB

Full HTT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HTT p.Ala1664= Likely benign ★ same residue
HTT c.889+6G>T Uncertain significance ★★ same type
HTT p.Ala2739Thr Uncertain significance ★★ same type
HTT p.Arg1654Trp Uncertain significance ★★ same type
HTT p.Arg1945Trp Uncertain significance ★★ same type
HTT p.Asp1157Gly Uncertain significance ★★ same type
HTT p.Asp920Asn Uncertain significance ★★ same type
HTT p.Glu449Ala Uncertain significance ★★ ⚠ same type

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/htt-p-ala1664val (accessed [today's date]).

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