Is HTT p.Thr486Ala (c.1456A>G) pathogenic?

HTT p.Thr486Ala (c.1456A>G) is classified Uncertain significance in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-09). AlphaMissense: likely benign (0.0722); Very rare (popmax 0.00669%, eas).

How common is HTT p.Thr486Ala (c.1456A>G) in the general population?

HTT p.Thr486Ala (c.1456A>G) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about HTT p.Thr486Ala (c.1456A>G)?

AlphaMissense predicts likely benign (score 0.0722) — an in-silico prediction, not a clinical call.

HTT p.Thr486Ala

c.1456A>G · rs548696125 · VCV1413947

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0722 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0722	likely benign
REVEL	0.056	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP 0.79, phastCons 0.98
Overall
CADD	16.1	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 0.00669% East Asian · 3/44,870 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000558% 9/1,614,104 alleles · very rare exomes 8/1,461,878 · genomes 1/152,226 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,957
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)	0.000424%	236,004

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.Thr486Ala
Coding: c.1456A>G
MANE Select: NM_001388492
dbSNP: rs548696125
Type: single nucleotide variant
Location: chr4:3127317 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB
Residue 486: an α-helix

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

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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-thr486ala (accessed [today's date]).

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