Is HTT p.Ala1417= (c.4251T>G) pathogenic?

HTT p.Ala1417= (c.4251T>G) is classified Likely benign in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-17). Very rare (popmax 0.00043%, nfe).

How common is HTT p.Ala1417= (c.4251T>G) in the general population?

HTT p.Ala1417= (c.4251T>G) is very rare (popmax 0.00043%, nfe) (gnomAD).

HTT p.Ala1417=

c.4251T>G · rs781216636 · VCV1970696

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00043%, nfe)

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 -0.94	GERP -4.2, phastCons 0.006
Overall
CADD	5.848	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00043% European (non-Finnish) · 5/1,163,566 alleles

Filtering AF 0.000126% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.2e-05%

Overall 0.000348% 5/1,436,584 alleles · very rare

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.Ala1417=
Coding: c.4251T>G
MANE Select: NM_001045 · reported on NM_001388492
dbSNP: rs781216636
Type: single nucleotide variant
Location: chr4:3174951 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB

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

Similar variants

HTT p.Ala1417Val Uncertain significance ★ ⚠ 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-ala1417 (accessed [today's date]).

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