Is TPH1 p.Pro262His (c.785C>A) pathogenic?

TPH1 p.Pro262His (c.785C>A) is classified Uncertain significance in TPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-31). AlphaMissense: likely pathogenic (0.9319); Absent from gnomAD v4.1.

How common is TPH1 p.Pro262His (c.785C>A) in the general population?

TPH1 p.Pro262His (c.785C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TPH1 p.Pro262His (c.785C>A)?

AlphaMissense predicts likely pathogenic (score 0.9319) — an in-silico prediction, not a clinical call.

TPH1 p.Pro262His

c.785C>A · rs2493991190 · VCV2554020

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9319 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9319	likely pathogenic
REVEL	0.906	moderately pathogenic-leaning
SaProt	LLR -14.76	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 20 kb · p 0.11 · regional, not allelic
Overall
CADD	31.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TPH1
Protein: p.Pro262His
Coding: c.785C>A
MANE Select: NM_004179
dbSNP: rs2493991190
Type: single nucleotide variant
Location: chr11:18026508 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.96 · 21 PDB

Full TPH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TPH1 p.Leu365= Benign ★★ same type
TPH1 p.Arg144His Uncertain significance ★ ⚠ same type
TPH1 p.Arg145Gln Uncertain significance ★ ⚠ same type
TPH1 p.Arg17Thr Uncertain significance ★ ⚠ same type
TPH1 p.Arg191Ser Uncertain significance ★ ⚠ same type
TPH1 p.Arg224Cys Uncertain significance ★ ⚠ same type
TPH1 p.Arg224His Uncertain significance ★ ⚠ same type
TPH1 p.Arg230Cys 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/tph1-p-pro262his (accessed [today's date]).

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