Is TPH1 p.Leu35Val (c.103C>G) pathogenic?

TPH1 p.Leu35Val (c.103C>G) is classified Uncertain significance in TPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-07). AlphaMissense: ambiguous (0.3785); Very rare (popmax 0.000424%, nfe).

How common is TPH1 p.Leu35Val (c.103C>G) in the general population?

TPH1 p.Leu35Val (c.103C>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about TPH1 p.Leu35Val (c.103C>G)?

AlphaMissense predicts ambiguous (score 0.3785) — an in-silico prediction, not a clinical call.

TPH1 p.Leu35Val

c.103C>G · rs762622414 · VCV2223368

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3785 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3785	ambiguous
REVEL	0.867	moderately pathogenic-leaning
SaProt	LLR -12.01	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 20 kb · p 0.11 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,178,946 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,611,484 alleles · very rare

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: TPH1
Protein: p.Leu35Val
Coding: c.103C>G
MANE Select: NM_004179
dbSNP: rs762622414
Type: single nucleotide variant
Location: chr11:18040660 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.96 · 21 PDB
Residue 35: the act domain

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-leu35val (accessed [today's date]).

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