Is HTT p.Gln36fs (c.105_106del) pathogenic?

HTT p.Gln36fs (c.105106del) is classified Benign in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2016-03-28). Common (popmax 10.7%, afr) — too common for a highly-penetrant pathogenic allele.

HTT p.Gln36fs

Q: How common is HTT p.Gln36fs (c.105_106del) in the general population?

HTT p.Gln36fs (c.105_106del) is common (popmax 10.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.105_106del · rs751281707 · VCV402952

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Common

common (popmax 10.7%, 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.
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 1.1	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 10.7% African / African-American · 6,819/63,518 alleles

Filtering AF 10.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.4%

Overall 2.71% 39,715/1,467,808 alleles · common exomes 28,106/1,327,640 · genomes 11,609/140,168 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.7%	9
Ashkenazi Jewishnot grpmax-eligible	5.28%	19
Middle Eastern	4.51%	22
Finnishnot grpmax-eligible	3.46%	29
Admixed American	3.38%	30
Remaining individualsnot grpmax-eligible	3.25%	31
European (non-Finnish)	2.22%	45
South Asian	1.65%	60
Amishnot grpmax-eligible	1.5%	67
East Asian	1.15%	87

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.Gln36fs
Coding: c.105_106del
MANE Select: NM_001388492
dbSNP: rs751281707
Type: Deletion
Location: chr4:3074924 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB
Residue 36: the 'disordered' region

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

Similar variants

HTT p.Gln36_Gln38del Benign/Likely benign ★★ same residue
HTT p.Gln36_Gln38dup Conflicting classifications of pathogenicity ★ 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-gln36fs (accessed [today's date]).

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