Is HTT p.Thr284Ala (c.850A>G) pathogenic?

HTT p.Thr284Ala (c.850A>G) is classified Uncertain significance in HTT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-23). AlphaMissense: likely benign (0.0892); Rare (popmax 0.148%, mid).

How common is HTT p.Thr284Ala (c.850A>G) in the general population?

HTT p.Thr284Ala (c.850A>G) is rare (popmax 0.148%, mid) (gnomAD).

What do computational predictors say about HTT p.Thr284Ala (c.850A>G)?

AlphaMissense predicts likely benign (score 0.0892) — an in-silico prediction, not a clinical call.

HTT p.Thr284Ala

c.850A>G · rs548352092 · VCV2654595

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0892 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.148%, mid)

Computational evidence

Protein change
AlphaMissense	0.0892	likely benign
REVEL	0.307	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.62 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.9	GERP 1.1, phastCons 0.99
Overall
CADD	17.82	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 0.148% Middle Eastern · 9/6,062 alleles

Filtering AF 0.0774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0578%

Overall 0.00322% 52/1,613,902 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.148%	674
Remaining individualsnot grpmax-eligible	0.0096%	10,416
African / African-American	0.00533%	18,763
Admixed American	0.00333%	30,010
European (non-Finnish)	0.00246%	40,681
Finnishnot grpmax-eligible	0.00156%	64,046
South Asian	0.0011%	91,072

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.Thr284Ala
Coding: c.850A>G
MANE Select: NM_001045 · reported on NM_001388492
dbSNP: rs548352092
Type: single nucleotide variant
Location: chr4:3115406 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB
Residue 284: 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-thr284ala (accessed [today's date]).

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