Is HTR2A p.Trp76Cys (c.228G>T) pathogenic?

HTR2A p.Trp76Cys (c.228G>T) is classified Uncertain significance in HTR2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: likely pathogenic (0.9556); Absent from gnomAD v4.1.

How common is HTR2A p.Trp76Cys (c.228G>T) in the general population?

HTR2A p.Trp76Cys (c.228G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HTR2A p.Trp76Cys (c.228G>T)?

AlphaMissense predicts likely pathogenic (score 0.9556) — an in-silico prediction, not a clinical call.

HTR2A p.Trp76Cys

c.228G>T · rs2542239129 · VCV3107496

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9556 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9556	likely pathogenic
REVEL	0.514	indeterminate
SaProt	LLR -9.29	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 60 kb · p 3.5e-12 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HTR2A
Protein: p.Trp76Cys
Coding: c.228G>T
MANE Select: NM_000621
dbSNP: rs2542239129
Type: single nucleotide variant
Location: chr13:46895679 (GRCh38)
Gene constraint: LOEUF 0.632 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 74.03 · 47 PDB

Full HTR2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HTR2A p.Ala447Val Likely benign ★★ same type
HTR2A p.Leu229= Benign/Likely benign ★★ same type
HTR2A p.Ser17= Benign ★★ same type
HTR2A p.Ser219= Likely benign ★★ same type
HTR2A p.Ser34= Likely benign ★★ same type
HTR2A p.Ser62= Likely benign ★★ same type
HTR2A c.412+1G>C Uncertain significance ★ same type
HTR2A p.Ala230Thr 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/htr2a-p-trp76cys (accessed [today's date]).

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