Is TPH1 p.Val177Ile (c.529G>A) pathogenic?

TPH1 p.Val177Ile (c.529G>A) is classified Likely benign in TPH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-01). AlphaMissense: likely benign (0.0895); Rare (popmax 0.384%, nfe).

How common is TPH1 p.Val177Ile (c.529G>A) in the general population?

TPH1 p.Val177Ile (c.529G>A) is rare (popmax 0.384%, nfe) (gnomAD).

What do computational predictors say about TPH1 p.Val177Ile (c.529G>A)?

AlphaMissense predicts likely benign (score 0.0895) — an in-silico prediction, not a clinical call.

TPH1 p.Val177Ile

c.529G>A · rs147638867 · VCV2641660

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0895 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.384%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0895	likely benign
REVEL	0.419	indeterminate
SaProt	LLR -9.31	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 1.8	GERP 0.26, phastCons 0.94
Regional constraint	o/e 0.93	unconstrained · MANE · 20 kb · p 0.11 · regional, not allelic
Overall
CADD	19.39	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 0.384% European (non-Finnish) · 4,526/1,179,952 alleles

Filtering AF 0.374% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.37%

Overall 0.315% 5,086/1,613,962 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.384%	261
Remaining individualsnot grpmax-eligible	0.261%	383
Admixed American	0.253%	395
South Asian	0.161%	620
Middle Eastern	0.0825%	1,212
Finnishnot grpmax-eligible	0.0687%	1,455
African / African-American	0.0653%	1,530

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.Val177Ile
Coding: c.529G>A
MANE Select: NM_004179
dbSNP: rs147638867
Type: single nucleotide variant
Location: chr11:18029303 (GRCh38)
Gene constraint: LOEUF 0.921 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.96 · 21 PDB
Residue 177: an α-helix

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-val177ile (accessed [today's date]).

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