Is HTR3D p.Ser49Pro (c.145T>C) pathogenic?

HTR3D p.Ser49Pro (c.145T>C) is classified Uncertain significance in HTR3D (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-16). AlphaMissense: likely benign (0.1301); Very rare (popmax 0.00196%, amr).

How common is HTR3D p.Ser49Pro (c.145T>C) in the general population?

HTR3D p.Ser49Pro (c.145T>C) is very rare (popmax 0.00196%, amr) (gnomAD).

What do computational predictors say about HTR3D p.Ser49Pro (c.145T>C)?

AlphaMissense predicts likely benign (score 0.1301) — an in-silico prediction, not a clinical call.

HTR3D p.Ser49Pro

c.145T>C · VCV3285048

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1301 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00196%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1301	likely benign
REVEL	0.236	benign-leaning
SaProt	LLR -6.65	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 -0.63
Regional constraint	o/e 0.88	unconstrained · MANE · 7,230 bp · p 0.0089 · regional, not allelic
Overall
CADD	10.98	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S110P vs ClinVar S49P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00196% Admixed American · 1/50,962 alleles

Overall 0.000129% 2/1,551,494 alleles · very rare exomes 1/1,399,368 · genomes 1/152,126 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00196%	50,962
Remaining individualsnot grpmax-eligible	0.00166%	60,094

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: HTR3D
Protein: p.Ser49Pro
Coding: c.145T>C
MANE Select: NM_001145143
Type: single nucleotide variant
Location: chr3:184036048 (GRCh38)
Gene constraint: LOEUF 1.281 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.01

Full HTR3D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HTR3D c.112-12C>A Uncertain significance ★ ⚠ same type
HTR3D c.112-17A>G Uncertain significance ★ ⚠ same type
HTR3D c.112-24C>G Uncertain significance ★ ⚠ same type
HTR3D c.66+1034A>G Uncertain significance ★ ⚠ same type
HTR3D c.66+1048C>G Uncertain significance ★ ⚠ same type
HTR3D c.66+1052C>A Uncertain significance ★ ⚠ same type
HTR3D c.66+1052C>G Uncertain significance ★ ⚠ same type
HTR3D c.66+1063C>G 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/htr3d-p-ser49pro (accessed [today's date]).

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