Is HTT p.Gln38fs (c.112dup) pathogenic?

HTT p.Gln38fs (c.112dup) is classified Likely benign in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-08). Ultra-rare (popmax 0.0282%, mid).

How common is HTT p.Gln38fs (c.112dup) in the general population?

HTT p.Gln38fs (c.112dup) is ultra-rare (popmax 0.0282%, mid) (gnomAD).

HTT p.Gln38fs

c.112dup · VCV4966126

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0282%, 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 1	GERP 0.14, phastCons 0.2
Overall
CADD	23.2	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 0.0282% Middle Eastern · 1/3,552 alleles

Filtering AF 0.000744% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000573%

Overall 0.00123% 16/1,302,662 alleles · ultra-rare exomes 10/1,176,882 · genomes 6/125,780 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0282%	3,552
African / African-American	0.00317%	31,515
European (non-Finnish)	0.00133%	74,965

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.Gln38fs
Coding: c.112dup
MANE Select: NM_001388492 · reported on NM_002111
Type: Duplication
Location: chr4:3074930 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB
Residue 38: the 'disordered' region

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

Similar variants

HTT p.Gln38_Pro39insGln Benign ★★ same residue
HTT p.Gln38_Pro39insGlnGlnGlnGlnGln Likely benign ★★ same residue
HTT p.Gln38_Pro39insGlnGlnGlnGlnGlnGlnGlnGlnGln Likely benign ★★ same residue
HTT p.Gln38_Pro39insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln Benign/Likely benign ★★ same residue
HTT p.Gln38_Pro39insGlnGlnGlnGlnGlnGlnGlnGlnGlnGln Conflicting classifications of pathogenicity ★ same residue
HTT p.Gln38_Pro39insGlnGlnGlnGln Likely benign ★ same residue
HTT p.Gln38_Pro39insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln Likely benign ★ same residue
HTT p.Gln38_Pro39insGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln Likely benign ★ same residue

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-gln38fs (accessed [today's date]).

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