Is HTT p.Pro40= (c.120A>G) pathogenic?

HTT p.Pro40= (c.120A>G) is classified Benign in HTT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-16). Common (popmax 34.6%, afr) — too common for a highly-penetrant pathogenic allele.

HTT p.Pro40=

Q: How common is HTT p.Pro40= (c.120A>G) in the general population?

HTT p.Pro40= (c.120A>G) is common (popmax 34.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.120A>G · VCV3910367

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 34.6%, 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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.2	GERP -0.67
Overall
CADD	4.084	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 34.6% African / African-American · 17,588/50,830 alleles

Filtering AF 34.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 34%

Overall 15.1% 172,129/1,142,354 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	37.4%	3
African / African-Americangrpmax	34.6%	3
East Asian	33.1%	3
Admixed American	22.9%	4
Amishnot grpmax-eligible	21.8%	5
Remaining individualsnot grpmax-eligible	16.6%	6
European (non-Finnish)	12.2%	8
South Asian	12.2%	8
Ashkenazi Jewishnot grpmax-eligible	10.7%	9
Middle Eastern	8.25%	12

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.Pro40=
Coding: c.120A>G
MANE Select: NM_001045 · reported on NM_001388492
Type: single nucleotide variant
Location: chr4:3074945 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB
Residue 40: the 'disordered' region

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

Similar variants

HTT p.Gln40_Pro41insGlnGlnGlnGlnGln Likely benign ★ same residue
HTT c.889+6G>T Uncertain significance ★★ same type
HTT p.Ala2739Thr Uncertain significance ★★ same type
HTT p.Arg1654Trp Uncertain significance ★★ same type
HTT p.Arg1945Trp Uncertain significance ★★ same type
HTT p.Asp1157Gly Uncertain significance ★★ same type
HTT p.Asp920Asn Uncertain significance ★★ same type
HTT p.Glu449Ala 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-pro40 (accessed [today's date]).

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