Is HTR2A p.Arg185His (c.554G>A) pathogenic?

HTR2A p.Arg185His (c.554G>A) is classified Uncertain significance in HTR2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-17). AlphaMissense: likely benign (0.2717); Ultra-rare (popmax 0.0165%, mid).

How common is HTR2A p.Arg185His (c.554G>A) in the general population?

HTR2A p.Arg185His (c.554G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about HTR2A p.Arg185His (c.554G>A)?

AlphaMissense predicts likely benign (score 0.2717) — an in-silico prediction, not a clinical call.

HTR2A p.Arg185His

c.554G>A · rs756580138 · VCV2269257

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2717 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2717	likely benign
REVEL	0.312	indeterminate
SaProt	LLR -8.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 60 kb · p 3.5e-12 · regional, not allelic
Overall
CADD	33.0	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000821% 12/1,461,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Finnishnot grpmax-eligible	0.00312%	32,018
European (non-Finnish)	0.000763%	131,115

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: HTR2A
Protein: p.Arg185His
Coding: c.554G>A
MANE Select: NM_000621
dbSNP: rs756580138
Type: single nucleotide variant
Location: chr13:46892449 (GRCh38)
Gene constraint: LOEUF 0.632 · pLI 0.36 (gnomAD)
Structure: AlphaFold pLDDT 74.03 · 47 PDB
Residue 185: a disulfide bond; an α-helix

Full HTR2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HTR2A p.Ala447Val Likely benign ★★ same type
HTR2A p.Leu229= Benign/Likely benign ★★ same type
HTR2A p.Ser17= Benign ★★ same type
HTR2A p.Ser219= Likely benign ★★ same type
HTR2A p.Ser34= Likely benign ★★ same type
HTR2A p.Ser62= Likely benign ★★ same type
HTR2A c.412+1G>C Uncertain significance ★ same type
HTR2A p.Ala230Thr 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/htr2a-p-arg185his (accessed [today's date]).

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