Is HTR2C p.Phe220= (c.660C>T) pathogenic?

HTR2C p.Phe220= (c.660C>T) is classified Likely benign in HTR2C (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-11-17). Ultra-rare (popmax 0.0372%, amr); Associated with HTR2C-related disorder.

What condition is associated with HTR2C p.Phe220= (c.660C>T)?

HTR2C p.Phe220= (c.660C>T) is associated with HTR2C-related disorder (ClinVar).

How common is HTR2C p.Phe220= (c.660C>T) in the general population?

HTR2C p.Phe220= (c.660C>T) is ultra-rare (popmax 0.0372%, amr) (gnomAD).

HTR2C p.Phe220=

c.660C>T · rs781957272 · VCV3044760

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0372%, amr)

Conditions

HTR2C-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.097	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.52	GERP 2.4, phastCons 0.025
Overall
CADD	9.816	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0372% Admixed American · 17/45,654 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0194%

Overall 0.0019% 23/1,208,785 alleles · ultra-rare exomes 21/1,097,613 · genomes 2/111,172 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0372%	2,686
East Asian	0.0119%	8,426
Remaining individualsnot grpmax-eligible	0.0021%	47,598
European (non-Finnish)	0.000112%	894,582

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.Phe220=
Coding: c.660C>T
MANE Select: NM_000868
dbSNP: rs781957272
Type: single nucleotide variant
Location: chrX:114906698 (GRCh38)
Structure: AlphaFold pLDDT 73.71 · 8 PDB
Residue 220: 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-phe220 (accessed [today's date]).

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