Is TMPRSS6 p.Ser234Phe (c.701C>T) pathogenic?

TMPRSS6 p.Ser234Phe (c.701C>T) is classified Uncertain significance in TMPRSS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-25). AlphaMissense: likely benign (0.1983); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with TMPRSS6 p.Ser234Phe (c.701C>T)?

TMPRSS6 p.Ser234Phe (c.701C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TMPRSS6 p.Ser234Phe (c.701C>T) in the general population?

TMPRSS6 p.Ser234Phe (c.701C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about TMPRSS6 p.Ser234Phe (c.701C>T)?

AlphaMissense predicts likely benign (score 0.1983) — an in-silico prediction, not a clinical call.

TMPRSS6 p.Ser234Phe

c.701C>T · rs1363548781 · VCV2479082

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1983 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1983	likely benign
REVEL	0.241	benign-leaning
SaProt	LLR -10.01	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.3	GERP 0.48, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.097 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S243F vs ClinVar S234F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,892 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00048% 7/1,459,672 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,892
European (non-Finnish)	0.000509%	196,560

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: TMPRSS6
Protein: p.Ser234Phe
Coding: c.701C>T
MANE Select: NM_001374504
dbSNP: rs1363548781
Type: single nucleotide variant
Location: chr22:37089713 (GRCh38)
Gene constraint: LOEUF 0.821 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.69 · 1 PDB
Residue 234: a UniProt-annotated variant site (in a breast cancer sample; somatic mutation); the cub 1 domain

Full TMPRSS6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMPRSS6 p.Ser234Thr Uncertain significance ★ ⚠ same residue
TMPRSS6 p.Ala164Thr Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Ala700Val Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Arg121His Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Arg251Gln Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Arg545Trp Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Arg780Gln Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Arg96His Uncertain significance ★★ ⚠ 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/tmprss6-p-ser234phe (accessed [today's date]).

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