Is HTT p.Leu168= (c.504C>T) pathogenic?

HTT p.Leu168= (c.504C>T) is classified Benign/Likely benign in HTT (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-06). Rare (popmax 0.344%, afr).

How common is HTT p.Leu168= (c.504C>T) in the general population?

HTT p.Leu168= (c.504C>T) is rare (popmax 0.344%, afr) (gnomAD).

HTT p.Leu168=

c.504C>T · rs200331534 · VCV1530595

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.344%, afr)

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 -1.7	GERP -4.3
Overall
CADD	2.879	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.344% African / African-American · 257/74,732 alleles

Filtering AF 0.309% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.296%

Overall 0.0205% 330/1,606,266 alleles · rare exomes 169/1,454,270 · genomes 161/151,996 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.344%	291
Middle Eastern	0.0497%	2,013
Admixed American	0.0217%	4,603
Remaining individualsnot grpmax-eligible	0.0145%	6,913
European (non-Finnish)	0.00409%	24,463

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.Leu168=
Coding: c.504C>T
MANE Select: NM_001388492
dbSNP: rs200331534
Type: single nucleotide variant
Location: chr4:3103859 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB
Residue 168: an α-helix

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

Similar variants

SLC6A4 p.Ile168Thr Uncertain significance ★ ⚠ same residue
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

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-leu168 (accessed [today's date]).

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