Is HTT p.Gln38Pro (c.113A>C) pathogenic?

HTT p.Gln38Pro (c.113A>C) is classified Benign in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-16). AlphaMissense: likely benign (0.0772); Common (popmax 22.5%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about HTT p.Gln38Pro (c.113A>C)?

AlphaMissense predicts likely benign (score 0.0772) — an in-silico prediction, not a clinical call.

HTT p.Gln38Pro

Q: How common is HTT p.Gln38Pro (c.113A>C) in the general population?

HTT p.Gln38Pro (c.113A>C) is common (popmax 22.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.113A>C · VCV3910363

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0772 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 22.5%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0772	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.23	GERP 0.045
Overall
CADD	9.647	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM Q36P vs ClinVar Q38P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 22.5% East Asian · 6,567/29,144 alleles

Filtering AF 22.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.9%

Overall 6.88% 86,152/1,251,750 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	23.7%	4
East Asiangrpmax	22.5%	4
African / African-American	18.5%	5
Amishnot grpmax-eligible	15.6%	6
Admixed American	12.4%	8
Remaining individualsnot grpmax-eligible	8.39%	12
South Asian	8.06%	12
Ashkenazi Jewishnot grpmax-eligible	6.94%	14
Middle Eastern	5.24%	19
European (non-Finnish)	4.74%	21

Finnish 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.Gln38Pro
Coding: c.113A>C
MANE Select: NM_001045 · reported on NM_002111
Type: single nucleotide variant
Location: chr4:3074932 (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-gln38pro (accessed [today's date]).

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