Is HTR2C p.Pro159Ser (c.475C>T) pathogenic?

HTR2C p.Pro159Ser (c.475C>T) is classified Uncertain significance in HTR2C (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-28). AlphaMissense: likely pathogenic (0.9984); Very rare (popmax 0.00435%, amr); Associated with HTR2C-related disorder.

What condition is associated with HTR2C p.Pro159Ser (c.475C>T)?

HTR2C p.Pro159Ser (c.475C>T) is associated with HTR2C-related disorder (ClinVar).

How common is HTR2C p.Pro159Ser (c.475C>T) in the general population?

HTR2C p.Pro159Ser (c.475C>T) is very rare (popmax 0.00435%, amr) (gnomAD).

What do computational predictors say about HTR2C p.Pro159Ser (c.475C>T)?

AlphaMissense predicts likely pathogenic (score 0.9984) — an in-silico prediction, not a clinical call.

HTR2C p.Pro159Ser

c.475C>T · VCV3358651

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9984 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00435%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

HTR2C-related disorder

Computational evidence

Protein change
AlphaMissense	0.9984	likely pathogenic · top 4% in HTR2C
REVEL	0.631	indeterminate
SaProt	LLR -13.00	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 5.8, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 59 kb · p 0.00044 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00435% Admixed American · 2/45,985 alleles

Filtering AF 0.000721% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00027%

Overall 0.000165% 2/1,210,867 alleles · very rare exomes 2/1,096,986 · genomes 0/113,881 · 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.Pro159Ser
Coding: c.475C>T
MANE Select: NM_000868
Type: single nucleotide variant
Location: chrX:114848128 (GRCh38)
Structure: AlphaFold pLDDT 73.71 · 8 PDB
Residue 159: an α-helix

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-pro159ser (accessed [today's date]).

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