Is HTR2C p.Pro256Ser (c.766C>T) pathogenic?

HTR2C p.Pro256Ser (c.766C>T) is classified Uncertain significance in HTR2C (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-08-09). AlphaMissense: likely benign (0.0777); Very rare (popmax 0.00123%, nfe); Associated with HTR2C-related disorder.

What condition is associated with HTR2C p.Pro256Ser (c.766C>T)?

HTR2C p.Pro256Ser (c.766C>T) is associated with HTR2C-related disorder (ClinVar).

How common is HTR2C p.Pro256Ser (c.766C>T) in the general population?

HTR2C p.Pro256Ser (c.766C>T) is very rare (popmax 0.00123%, nfe) (gnomAD).

What do computational predictors say about HTR2C p.Pro256Ser (c.766C>T)?

AlphaMissense predicts likely benign (score 0.0777) — an in-silico prediction, not a clinical call.

HTR2C p.Pro256Ser

c.766C>T · VCV3350865

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0777 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00123%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

HTR2C-related disorder

Computational evidence

Protein change
AlphaMissense	0.0777	likely benign
REVEL	0.265	benign-leaning
SaProt	LLR -4.94	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 0.8	GERP 3
Regional constraint	o/e 0.78	unconstrained · MANE · 59 kb · p 0.00044 · regional, not allelic
Overall
CADD	8.87	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

Grpmax group 0.00123% European (non-Finnish) · 11/895,194 alleles

Filtering AF 0.000659% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000482%

Overall 0.000908% 11/1,210,833 alleles · very rare exomes 11/1,097,948 · genomes 0/112,885 · joint denominator

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: HTR2C
Protein: p.Pro256Ser
Coding: c.766C>T
MANE Select: NM_000868
Type: single nucleotide variant
Location: chrX:114906804 (GRCh38)
Structure: AlphaFold pLDDT 73.71 · 8 PDB

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

Disease context

HTR2C-related disorder

Similar variants

HTR2C p.Val8= Uncertain significance ★ same condition
HTR2C c.349+2T>C Uncertain significance same condition
HTR2C p.Arg288Ter Uncertain significance same condition
HTR2C p.Arg295Cys Uncertain significance ⚠ same condition
HTR2C p.Arg295Gly Uncertain significance ⚠ same condition
HTR2C p.Arg400Ser Uncertain significance ⚠ same condition
HTR2C p.Arg454Met Uncertain significance ⚠ same condition
HTR2C p.Asn166Ser Uncertain significance ⚠ 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/htr2c-p-pro256ser (accessed [today's date]).

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