Is HTR2C p.Pro394Ser (c.1180C>T) pathogenic?

HTR2C p.Pro394Ser (c.1180C>T) is classified Uncertain significance in HTR2C (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-29). AlphaMissense: likely benign (0.0891); Absent from gnomAD v4.1.

How common is HTR2C p.Pro394Ser (c.1180C>T) in the general population?

HTR2C p.Pro394Ser (c.1180C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HTR2C p.Pro394Ser (c.1180C>T)?

AlphaMissense predicts likely benign (score 0.0891) — an in-silico prediction, not a clinical call.

HTR2C p.Pro394Ser

c.1180C>T · rs2522061579 · VCV2607228

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0891 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0891	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 5.3, phastCons 0.98
Regional constraint	o/e 0.78	unconstrained · MANE · 59 kb · p 0.00044 · regional, not allelic
Overall
CADD	14.86	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 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: HTR2C
Protein: p.Pro394Ser
Coding: c.1180C>T
MANE Select: NM_000868
dbSNP: rs2522061579
Type: single nucleotide variant
Location: chrX:114907218 (GRCh38)
Structure: AlphaFold pLDDT 73.71 · 8 PDB

Full HTR2C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HTR2C p.Ser23= Benign ★★ same type
HTR2C p.Ala278Gly Uncertain significance ★ ⚠ same type
HTR2C p.Ala31Val Uncertain significance ★ ⚠ same type
HTR2C p.Arg409Lys Uncertain significance ★ ⚠ same type
HTR2C p.Arg417Gln Uncertain significance ★ ⚠ same type
HTR2C p.Arg454Lys Uncertain significance ★ ⚠ same type
HTR2C p.Asp211Asn Uncertain significance ★ ⚠ same type
HTR2C p.Asp262Val 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/htr2c-p-pro394ser (accessed [today's date]).

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