Is HTT p.Arg1793Trp (c.5377C>T) pathogenic?

HTT p.Arg1793Trp (c.5377C>T) is classified Uncertain significance in HTT (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-14). AlphaMissense: likely pathogenic (0.6251); Very rare (popmax 0.00167%, amr).

How common is HTT p.Arg1793Trp (c.5377C>T) in the general population?

HTT p.Arg1793Trp (c.5377C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about HTT p.Arg1793Trp (c.5377C>T)?

AlphaMissense predicts likely pathogenic (score 0.6251) — an in-silico prediction, not a clinical call.

HTT p.Arg1793Trp

c.5377C>T · rs1196905887 · VCV1480301

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6251 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.6251	likely pathogenic
REVEL	0.289	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.4, phastCons 1
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,000 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000496% 8/1,613,628 alleles · very rare exomes 6/1,461,462 · genomes 2/152,166 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,000
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.000509%	196,648

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.Arg1793Trp
Coding: c.5377C>T
MANE Select: NM_001388492
dbSNP: rs1196905887
Type: single nucleotide variant
Location: chr4:3199740 (GRCh38)
Structure: AlphaFold pLDDT 85.38 · 30 PDB

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

Similar variants

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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
HTT p.Gly2084Arg 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-arg1793trp (accessed [today's date]).

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