Is HTR2C p.Pro128= (c.384C>T) pathogenic?

HTR2C p.Pro128= (c.384C>T) is classified Likely benign in HTR2C (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-29). Very rare (popmax 0.00176%, sas); Associated with HTR2C-related disorder.

What condition is associated with HTR2C p.Pro128= (c.384C>T)?

HTR2C p.Pro128= (c.384C>T) is associated with HTR2C-related disorder (ClinVar).

How common is HTR2C p.Pro128= (c.384C>T) in the general population?

HTR2C p.Pro128= (c.384C>T) is very rare (popmax 0.00176%, sas) (gnomAD).

HTR2C p.Pro128=

c.384C>T · VCV3352988

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00176%, sas)

Conditions

HTR2C-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.23	GERP 1.4, phastCons 0.98
Overall
CADD	12.07	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00176% South Asian · 1/56,867 alleles

Filtering AF 0.000164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000119%

Overall 0.000496% 6/1,209,333 alleles · very rare exomes 6/1,095,743 · genomes 0/113,590 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00176%	56,867
European (non-Finnish)	0.00056%	178,712

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.Pro128=
Coding: c.384C>T
MANE Select: NM_000868
Type: single nucleotide variant
Location: chrX:114848037 (GRCh38)
Structure: AlphaFold pLDDT 73.71 · 8 PDB
Residue 128: 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-pro128 (accessed [today's date]).

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