Is HTT p.Pro41Gln (c.122C>A) pathogenic?

HTT p.Pro41Gln (c.122C>A) is classified Uncertain significance in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: likely benign (0.0797); Ultra-rare (popmax 0.0398%, sas); Associated with Inborn genetic diseases.

What condition is associated with HTT p.Pro41Gln (c.122C>A)?

HTT p.Pro41Gln (c.122C>A) is associated with Inborn genetic diseases (ClinVar).

How common is HTT p.Pro41Gln (c.122C>A) in the general population?

HTT p.Pro41Gln (c.122C>A) is ultra-rare (popmax 0.0398%, sas) (gnomAD).

What do computational predictors say about HTT p.Pro41Gln (c.122C>A)?

AlphaMissense predicts likely benign (score 0.0797) — an in-silico prediction, not a clinical call.

HTT p.Pro41Gln

c.122C>A · rs1261369311 · VCV2350932

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0797 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0398%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0797	likely benign
REVEL	0.009	strongly 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 -0.3	GERP 0.37, phastCons 0.004
Overall
CADD	12.79	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0398% South Asian · 28/70,372 alleles

Filtering AF 0.0282% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0243%

Overall 0.00615% 83/1,349,448 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0398%	2,513
Admixed American	0.0174%	5,733
East Asian	0.00614%	16,297
European (non-Finnish)	0.00418%	23,901
Ashkenazi Jewishnot grpmax-eligible	0.00411%	24,310
Finnishnot grpmax-eligible	0.00259%	38,562
African / African-American	0.00168%	59,518

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.Pro41Gln
Coding: c.122C>A
MANE Select: NM_001045 · reported on NM_001388492
dbSNP: rs1261369311
Type: single nucleotide variant
Location: chr4:3074947 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB
Residue 41: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HTT p.Arg416Cys Uncertain significance ★ ⚠ same condition
HTT p.Gln29Pro Uncertain significance ★ ⚠ same condition
HTT p.Gln31Pro Conflicting classifications of pathogenicity ★ ⚠ same condition
HTT p.Gln35Pro Uncertain significance ★ ⚠ same condition
HTT p.Pro3007Leu Uncertain significance ★ same condition
HTT p.Thr1720Ser Uncertain significance ★ ⚠ same condition
HTT p.Val1484Glu Uncertain significance ★ same condition
HTT c.889+6G>T 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-pro41gln (accessed [today's date]).

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