Is HTT p.Ser475Thr (c.1424G>C) pathogenic?

HTT p.Ser475Thr (c.1424G>C) is classified Uncertain significance in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-24). AlphaMissense: likely benign (0.0636); Very rare (popmax 0.00161%, nfe).

How common is HTT p.Ser475Thr (c.1424G>C) in the general population?

HTT p.Ser475Thr (c.1424G>C) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about HTT p.Ser475Thr (c.1424G>C)?

AlphaMissense predicts likely benign (score 0.0636) — an in-silico prediction, not a clinical call.

HTT p.Ser475Thr

c.1424G>C · rs376114909 · VCV1449701

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0636 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0636	likely benign
REVEL	0.079	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 5	GERP 0.67, phastCons 0.95
Overall
CADD	12.39	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 0.00161% European (non-Finnish) · 19/1,179,898 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00124% 20/1,614,096 alleles · very rare exomes 20/1,461,710 · genomes 0/152,386 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00161%	62,100
African / African-American	0.00133%	75,070

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.Ser475Thr
Coding: c.1424G>C
MANE Select: NM_001388492
dbSNP: rs376114909
Type: single nucleotide variant
Location: chr4:3127285 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB
Residue 475: an α-helix

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

Similar variants

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
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-ser475thr (accessed [today's date]).

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