Is TGFB3 p.Phe202Ser (c.605T>C) pathogenic?

TGFB3 p.Phe202Ser (c.605T>C) is classified Uncertain significance in TGFB3 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-04-26). AlphaMissense: likely pathogenic (0.9883); Absent from gnomAD v4.1; Associated with Rienhoff syndrome.

What condition is associated with TGFB3 p.Phe202Ser (c.605T>C)?

TGFB3 p.Phe202Ser (c.605T>C) is associated with Rienhoff syndrome (ClinVar).

How common is TGFB3 p.Phe202Ser (c.605T>C) in the general population?

TGFB3 p.Phe202Ser (c.605T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TGFB3 p.Phe202Ser (c.605T>C)?

AlphaMissense predicts likely pathogenic (score 0.9883) — an in-silico prediction, not a clinical call.

TGFB3 p.Phe202Ser

c.605T>C · rs2035285904 · VCV1020029

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9883 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Rienhoff syndrome

Computational evidence

Protein change
AlphaMissense	0.9883	likely pathogenic · top 10% in TGFB3
REVEL	0.894	moderately pathogenic-leaning
SaProt	LLR -13.54	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 22 kb · p 8.8e-12 · regional, not allelic
Overall
CADD	25.9	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: TGFB3
Protein: p.Phe202Ser
Coding: c.605T>C
MANE Select: NM_003239
dbSNP: rs2035285904
Type: single nucleotide variant
Location: chr14:75971167 (GRCh38)
Gene constraint: LOEUF 0.249 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.48 · 11 PDB

Full TGFB3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Rienhoff syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TGFB3 p.Phe202Val Uncertain significance ★★ ⚠ same residue
TGFB3 c.517-2A>G Likely pathogenic ★★ same condition
TGFB3 c.646+1G>C Likely pathogenic ★★ same condition
TGFB3 c.926+1G>A Likely pathogenic ★★ same condition
TGFB3 c.927-1G>C Likely pathogenic ★★ same condition
TGFB3 p.Arg148Ter Pathogenic/Likely pathogenic ★★ same condition
TGFB3 p.Arg300Gln Pathogenic ★★ same condition
TGFB3 p.Arg300Trp Pathogenic/Likely pathogenic ★★ same condition

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/tgfb3-p-phe202ser (accessed [today's date]).

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