Is TMPRSS2 p.Cys244Phe (c.731G>T) pathogenic?

TMPRSS2 p.Cys244Phe (c.731G>T) is classified Uncertain significance in TMPRSS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-18). AlphaMissense: likely pathogenic (0.9646); Very rare (popmax 0.00224%, eas).

How common is TMPRSS2 p.Cys244Phe (c.731G>T) in the general population?

TMPRSS2 p.Cys244Phe (c.731G>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about TMPRSS2 p.Cys244Phe (c.731G>T)?

AlphaMissense predicts likely pathogenic (score 0.9646) — an in-silico prediction, not a clinical call.

TMPRSS2 p.Cys244Phe

c.731G>T · rs762050506 · VCV2255608

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9646 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9646	likely pathogenic · top 10% in TMPRSS2
REVEL	0.488	indeterminate
SaProt	LLR -13.41	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP 0.86, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 32 kb · p 0.32 · regional, not allelic
Overall
CADD	23.7	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

Grpmax group 0.00224% East Asian · 1/44,636 alleles

Overall 6.88e-05% 1/1,454,202 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: TMPRSS2
Protein: p.Cys244Phe
Coding: c.731G>T
MANE Select: NM_005656
dbSNP: rs762050506
Type: single nucleotide variant
Location: chr21:41473493 (GRCh38)
Gene constraint: LOEUF 0.991 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 34 PDB
Residue 244: a disulfide bond

Full TMPRSS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TMPRSS2 p.Ala216= Benign ★★ same type
TMPRSS2 p.Tyr180= Benign ★★ same type
TMPRSS2 p.Val160Met Benign ★★ same type
TMPRSS2 p.Ala490Gly Uncertain significance ★ ⚠ same type
TMPRSS2 p.Arg470Gly Uncertain significance ★ ⚠ same type
TMPRSS2 p.Asn249Asp Uncertain significance ★ ⚠ same type
TMPRSS2 p.Glu260Lys Uncertain significance ★ ⚠ same type
TMPRSS2 p.Glu376Lys 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/tmprss2-p-cys244phe (accessed [today's date]).

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