Is TST p.Phe216Cys (c.647T>G) pathogenic?

TST p.Phe216Cys (c.647T>G) is classified Uncertain significance in TST (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). AlphaMissense: ambiguous (0.5109); Very rare (popmax 0.00267%, afr).

How common is TST p.Phe216Cys (c.647T>G) in the general population?

TST p.Phe216Cys (c.647T>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about TST p.Phe216Cys (c.647T>G)?

AlphaMissense predicts ambiguous (score 0.5109) — an in-silico prediction, not a clinical call.

TST p.Phe216Cys

c.647T>G · VCV4600065

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5109 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
AlphaMissense	0.5109	ambiguous
REVEL	0.446	indeterminate
SaProt	LLR -7.45	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,702 bp · p 0.51 · regional, not allelic
Overall
CADD	25.5	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 0.00267% African / African-American · 2/74,912 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00031% 5/1,613,790 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,456
European (non-Finnish)	0.000254%	393,329

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: TST
Protein: p.Phe216Cys
Coding: c.647T>G
MANE Select: NM_003312
Type: single nucleotide variant
Location: chr22:37011274 (GRCh38)
Gene constraint: LOEUF 1.478 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.50 · 1 PDB
Residue 216: the rhodanese 2 domain; an α-helix

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

Similar variants

TST p.Arg132Trp Uncertain significance ★ ⚠ same type
TST p.Arg183Ser Uncertain significance ★ ⚠ same type
TST p.Arg187Leu Uncertain significance ★ ⚠ same type
TST p.Arg206His Uncertain significance ★ ⚠ same type
TST p.Arg230Cys Uncertain significance ★ ⚠ same type
TST p.Arg230His Uncertain significance ★ ⚠ same type
TST p.Arg249Cys Uncertain significance ★ ⚠ same type
TST p.Arg282Gln 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/tst-p-phe216cys (accessed [today's date]).

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