Is HTT p.Gln37fs (c.108_109del) pathogenic?

HTT p.Gln37fs (c.108109del) is classified Likely benign in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). Rare (popmax 0.349%, mid).

How common is HTT p.Gln37fs (c.108_109del) in the general population?

HTT p.Gln37fs (c.108_109del) is rare (popmax 0.349%, mid) (gnomAD).

HTT p.Gln37fs

c.108_109del · VCV4966123

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.349%, mid)

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 0.36	GERP -0.28, phastCons 1
Overall
CADD	22.4	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 0.349% Middle Eastern · 15/4,298 alleles

Filtering AF 0.215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.174%

Overall 0.106% 1,550/1,467,200 alleles · rare exomes 1,321/1,326,022 · genomes 229/141,178 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.349%	287
Finnishnot grpmax-eligible	0.34%	294
Ashkenazi Jewishnot grpmax-eligible	0.212%	471
Remaining individualsnot grpmax-eligible	0.127%	790
European (non-Finnish)	0.104%	961
Admixed American	0.0992%	1,009
African / African-American	0.0735%	1,361
South Asian	0.0139%	7,200

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.Gln37fs
Coding: c.108_109del
MANE Select: NM_001388492
Type: Deletion
Location: chr4:3074927 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB
Residue 37: the 'disordered' region

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

Similar variants

HTT p.Gln37= Likely benign ★ same residue
HTT p.Gln37_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-gln37fs (accessed [today's date]).

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