Is TMPRSS6 p.Arg88Cys (c.262C>T) pathogenic?

TMPRSS6 p.Arg88Cys (c.262C>T) is classified Uncertain significance in TMPRSS6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-29). AlphaMissense: likely benign (0.1721); Ultra-rare (popmax 0.0828%, afr); Associated with IRIDA syndrome.

What condition is associated with TMPRSS6 p.Arg88Cys (c.262C>T)?

TMPRSS6 p.Arg88Cys (c.262C>T) is associated with IRIDA syndrome (ClinVar).

How common is TMPRSS6 p.Arg88Cys (c.262C>T) in the general population?

TMPRSS6 p.Arg88Cys (c.262C>T) is ultra-rare (popmax 0.0828%, afr) (gnomAD).

How is IRIDA syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TMPRSS6 p.Arg88Cys (c.262C>T)?

AlphaMissense predicts likely benign (score 0.1721) — an in-silico prediction, not a clinical call.

TMPRSS6 p.Arg88Cys

c.262C>T · rs143182343 · VCV2892219

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1721 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0828%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

IRIDA syndrome

Computational evidence

Protein change
AlphaMissense	0.1721	likely benign
REVEL	0.302	indeterminate
SaProt	LLR -11.05	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.097 · regional, not allelic
Overall
CADD	33.0	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 R97C vs ClinVar R88C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0828% African / African-American · 62/74,846 alleles

Filtering AF 0.0662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0603%

Overall 0.00496% 80/1,613,952 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0828%	1,207
East Asian	0.00445%	22,450
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.00119%	84,287
South Asian	0.0011%	91,076

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.Arg88Cys
Coding: c.262C>T
MANE Select: NM_001374504
dbSNP: rs143182343
Type: single nucleotide variant
Location: chr22:37098490 (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 88: the sea domain; a β-strand

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

Disease context

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

For IRIDA syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TMPRSS6 p.Arg88His Uncertain significance ★ ⚠ same residue
TMPRSS6 c.1342+1G>A Pathogenic/Likely pathogenic ★★ same condition
TMPRSS6 p.Arg590Ter Pathogenic/Likely pathogenic ★★ same condition
TMPRSS6 p.Asp512Asn Likely pathogenic ★★ same condition
TMPRSS6 p.Gly433Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
TMPRSS6 p.Ser552Ter Pathogenic ★★ same condition
TMPRSS6 p.Tyr346Ter Likely pathogenic ★★ same condition
TMPRSS6 p.Asp466Asn 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-arg88cys (accessed [today's date]).

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