Is HTT p.Thr396= (c.1188C>T) pathogenic?

HTT p.Thr396= (c.1188C>T) is classified Benign in HTT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-02). Common (popmax 13.3%, afr) — too common for a highly-penetrant pathogenic allele.

HTT p.Thr396=

Q: How common is HTT p.Thr396= (c.1188C>T) in the general population?

HTT p.Thr396= (c.1188C>T) is common (popmax 13.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1188C>T · rs1065745 · VCV1600856

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 13.3%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.004	GERP -0.43, phastCons 0.001
Overall
CADD	9.346	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13.3% African / African-American · 9,945/74,998 alleles

Filtering AF 13% ClinGen BA1/BS1 input FAF95, joint · FAF99 13%

Overall 4.56% 73,521/1,613,760 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	13.3%	8
South Asian	7.01%	14
Middle Eastern	6.44%	16
Finnishnot grpmax-eligible	6.28%	16
Remaining individualsnot grpmax-eligible	4.81%	21
European (non-Finnish)	3.98%	25
Ashkenazi Jewishnot grpmax-eligible	3.24%	31
Admixed American	2.73%	37
Amishnot grpmax-eligible	1.21%	83
East Asian	0.437%	229

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.Thr396=
Coding: c.1188C>T
MANE Select: NM_001045 · reported on NM_001388492
dbSNP: rs1065745
Type: single nucleotide variant
Location: chr4:3121347 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB
Residue 396: 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-thr396 (accessed [today's date]).

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