Is HTT p.Gln38del (c.54GCA[18]) pathogenic?

HTT p.Gln38del (c.54GCA[18]) is classified Benign in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2016-03-28). Low-frequency (popmax 2.89%, mid).

How common is HTT p.Gln38del (c.54GCA[18]) in the general population?

HTT p.Gln38del (c.54GCA[18]) is low-frequency (popmax 2.89%, mid) (gnomAD).

HTT p.Gln38del

c.54GCA[18] · rs754481229 · VCV402953

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

low-frequency (popmax 2.89%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.36	GERP -0.28, phastCons 1
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(CAG)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.89% Middle Eastern · 124/4,296 alleles

Filtering AF 2.47% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.32%

Overall 1.18% 17,302/1,466,800 alleles · low-frequency exomes 15,025/1,325,628 · genomes 2,277/141,172 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	4.02%	25
Middle Easterngrpmax	2.89%	35
Remaining individualsnot grpmax-eligible	1.36%	73
European (non-Finnish)	1.25%	80
Amishnot grpmax-eligible	1.08%	93
Admixed American	0.81%	123
Finnishnot grpmax-eligible	0.676%	148
South Asian	0.648%	154
African / African-American	0.438%	228

Ashkenazi Jewish 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.Gln38del
Coding: c.54GCA[18]
MANE Select: NM_001388492
dbSNP: rs754481229
Type: Deletion
Location: chr4:3074927 (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-gln38del (accessed [today's date]).

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