Is HTT p.Val1546= (c.4638C>G) pathogenic?

HTT p.Val1546= (c.4638C>G) is classified Benign/Likely benign in HTT (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-06-01). Rare (popmax 0.617%, afr); Associated with Huntington disease.

What condition is associated with HTT p.Val1546= (c.4638C>G)?

HTT p.Val1546= (c.4638C>G) is associated with Huntington disease, Lopes-Maciel-Rodan syndrome (ClinVar).

How common is HTT p.Val1546= (c.4638C>G) in the general population?

HTT p.Val1546= (c.4638C>G) is rare (popmax 0.617%, afr) (gnomAD).

How is Huntington disease inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

HTT p.Val1546=

c.4638C>G · rs116293982 · VCV1671702

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.617%, afr)

Conditions

Huntington disease

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 -0.34	GERP -4.5, phastCons 0.11
Overall
CADD	2.596	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.617% African / African-American · 461/74,770 alleles

Filtering AF 0.57% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.552%

Overall 0.0333% 536/1,611,820 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.617%	162
Admixed American	0.0402%	2,489
Remaining individualsnot grpmax-eligible	0.0352%	2,838
European (non-Finnish)	0.00237%	42,108
South Asian	0.0011%	90,696

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.Val1546=
Coding: c.4638C>G
MANE Select: NM_001045 · reported on NM_001388492
dbSNP: rs116293982
Type: single nucleotide variant
Location: chr4:3180540 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB

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

Disease context

Huntington disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lopes-Maciel-Rodan syndrome

For Huntington disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Elderly
Prevalence: 1-9 / 100 000 (Greece)

Similar variants

HTT p.Asp920Asn Uncertain significance ★★ same condition
HTT p.Gly2084Arg Uncertain significance ★★ same condition
HTT p.Gly2968Asp Uncertain significance ★★ same condition
HTT p.Leu1237Ile Uncertain significance ★★ ⚠ same condition
HTT p.Pro703Leu Uncertain significance ★★ ⚠ same condition
HTT p.Val2500Ile Uncertain significance ★★ ⚠ same condition
HTT c.7765+10G>A Benign/Likely benign ★★ same condition
HTT p.Thr1260Met Benign ★★ same condition

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-val1546 (accessed [today's date]).

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