Is HTT p.Arg416Cys (c.1246C>T) pathogenic?

HTT p.Arg416Cys (c.1246C>T) is classified Uncertain significance in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). AlphaMissense: likely benign (0.1736); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with HTT p.Arg416Cys (c.1246C>T)?

HTT p.Arg416Cys (c.1246C>T) is associated with Inborn genetic diseases (ClinVar).

How common is HTT p.Arg416Cys (c.1246C>T) in the general population?

HTT p.Arg416Cys (c.1246C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about HTT p.Arg416Cys (c.1246C>T)?

AlphaMissense predicts likely benign (score 0.1736) — an in-silico prediction, not a clinical call.

HTT p.Arg416Cys

c.1246C>T · rs367833914 · VCV521676

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1736 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1736	likely benign
REVEL	0.278	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 7.6	GERP 1.7, phastCons 1
Overall
CADD	32.0	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 0.00267% African / African-American · 2/74,858 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000496% 8/1,613,734 alleles · very rare exomes 6/1,461,662 · genomes 2/152,072 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,429
Remaining individualsnot grpmax-eligible	0.0016%	62,474
European (non-Finnish)	0.000424%	235,971

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.Arg416Cys
Coding: c.1246C>T
MANE Select: NM_001388492
dbSNP: rs367833914
Type: single nucleotide variant
Location: chr4:3121405 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB
Residue 416: an α-helix

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.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.Pro41Gln 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-arg416cys (accessed [today's date]).

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