Is HTT p.Ile1493Val (c.4477A>G) pathogenic?

HTT p.Ile1493Val (c.4477A>G) is classified Uncertain significance in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-16). AlphaMissense: likely benign (0.0694); Ultra-rare (popmax 0.0129%, nfe).

How common is HTT p.Ile1493Val (c.4477A>G) in the general population?

HTT p.Ile1493Val (c.4477A>G) is ultra-rare (popmax 0.0129%, nfe) (gnomAD).

What do computational predictors say about HTT p.Ile1493Val (c.4477A>G)?

AlphaMissense predicts likely benign (score 0.0694) — an in-silico prediction, not a clinical call.

HTT p.Ile1493Val

c.4477A>G · rs765822494 · VCV1446781

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0694 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0129%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0694	likely benign
REVEL	0.118	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 9.1	GERP 1.1, phastCons 1
Overall
CADD	21.3	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 0.0129% European (non-Finnish) · 152/1,175,202 alleles

Filtering AF 0.0113% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00989% 159/1,608,166 alleles · ultra-rare exomes 155/1,455,928 · genomes 4/152,238 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0129%	7,732
African / African-American	0.00669%	14,955
Remaining individualsnot grpmax-eligible	0.00321%	31,153

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.Ile1493Val
Coding: c.4477A>G
MANE Select: NM_001388492
dbSNP: rs765822494
Type: single nucleotide variant
Location: chr4:3178311 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB

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

Similar variants

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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
HTT p.Gly2084Arg 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-ile1493val (accessed [today's date]).

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