Is HTT p.Gln35fs (c.102_103del) pathogenic?

HTT p.Gln35fs (c.102103del) is classified Likely benign in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). Rare (popmax 0.715%, afr).

How common is HTT p.Gln35fs (c.102_103del) in the general population?

HTT p.Gln35fs (c.102_103del) is rare (popmax 0.715%, afr) (gnomAD).

HTT p.Gln35fs

c.102_103del · rs750382879 · VCV4966120

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.715%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.9	GERP -0.28, phastCons 1
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(CAG)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.715% African / African-American · 476/66,556 alleles

Filtering AF 0.662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.641%

Overall 0.163% 2,413/1,477,916 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.73%	58
African / African-Americangrpmax	0.715%	140
Finnishnot grpmax-eligible	0.243%	412
Middle Eastern	0.233%	430
South Asian	0.228%	439
Remaining individualsnot grpmax-eligible	0.213%	469
Admixed American	0.211%	474
Ashkenazi Jewishnot grpmax-eligible	0.187%	535
East Asian	0.148%	677
European (non-Finnish)	0.116%	860

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Gln35fs
Coding: c.102_103del
MANE Select: NM_001045 · reported on NM_001388492
dbSNP: rs750382879
Type: Deletion
Location: chr4:3074921 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB
Residue 35: the 'disordered' region

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

Similar variants

HTT p.Gln35Pro Uncertain significance ★ ⚠ same residue
HTT p.Gln35_Gln38del Likely benign ★ same residue
HTT c.5369-9del Likely benign ★★ same type
HTT p.Gln33fs Likely pathogenic ★ same type
HTT p.Gly697fs Pathogenic ★ same type
HTT p.Ser1941fs Pathogenic ★ same type
HTT c.2099-21_2099-13del Uncertain significance ★ same type
HTT c.747+4del 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-gln35fs (accessed [today's date]).

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