Is TMPRSS6 p.Cys236Ser (c.707G>C) pathogenic?

TMPRSS6 p.Cys236Ser (c.707G>C) is classified Uncertain significance in TMPRSS6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-06). AlphaMissense: likely pathogenic (0.9778); Ultra-rare (popmax 0.0414%, afr); Associated with Inborn genetic diseases.

What condition is associated with TMPRSS6 p.Cys236Ser (c.707G>C)?

TMPRSS6 p.Cys236Ser (c.707G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TMPRSS6 p.Cys236Ser (c.707G>C) in the general population?

TMPRSS6 p.Cys236Ser (c.707G>C) is ultra-rare (popmax 0.0414%, afr) (gnomAD).

What do computational predictors say about TMPRSS6 p.Cys236Ser (c.707G>C)?

AlphaMissense predicts likely pathogenic (score 0.9778) — an in-silico prediction, not a clinical call.

TMPRSS6 p.Cys236Ser

c.707G>C · rs763489601 · VCV2366567

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9778 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0414%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9778	likely pathogenic · top 6% in TMPRSS6
REVEL	0.743	pathogenic-leaning
SaProt	LLR -13.35	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 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.097 · regional, not allelic
Overall
CADD	25.3	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM C245S vs ClinVar C236S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0414% African / African-American · 31/74,920 alleles

Filtering AF 0.0299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.0023% 37/1,611,768 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0414%	2,417
Remaining individualsnot grpmax-eligible	0.00642%	15,582
Admixed American	0.00334%	29,927

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.Cys236Ser
Coding: c.707G>C
MANE Select: NM_001374504
dbSNP: rs763489601
Type: single nucleotide variant
Location: chr22:37089707 (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 236: the cub 1 domain; an α-helix

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.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
TMPRSS6 p.Asp600Val 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-cys236ser (accessed [today's date]).

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