Is TMPRSS6 p.Ala22Val (c.65C>T) pathogenic?

TMPRSS6 p.Ala22Val (c.65C>T) is classified Uncertain significance in TMPRSS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-24). AlphaMissense: likely benign (0.105); Ultra-rare (popmax 0.0395%, sas); Associated with IRIDA syndrome.

What condition is associated with TMPRSS6 p.Ala22Val (c.65C>T)?

TMPRSS6 p.Ala22Val (c.65C>T) is associated with IRIDA syndrome (ClinVar).

How common is TMPRSS6 p.Ala22Val (c.65C>T) in the general population?

TMPRSS6 p.Ala22Val (c.65C>T) is ultra-rare (popmax 0.0395%, sas) (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.Ala22Val (c.65C>T)?

AlphaMissense predicts likely benign (score 0.105) — an in-silico prediction, not a clinical call.

TMPRSS6 p.Ala22Val

c.65C>T · rs200558933 · VCV2437123

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.105 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0395%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

IRIDA syndrome

Computational evidence

Protein change
AlphaMissense	0.105	likely benign
REVEL	0.263	benign-leaning
SaProt	LLR -6.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 1.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.097 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 A31V vs ClinVar A22V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0395% South Asian · 36/91,082 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.00527% 85/1,614,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0395%	2,530
African / African-American	0.0253%	3,949
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
Remaining individualsnot grpmax-eligible	0.0048%	20,836
Admixed American	0.00333%	30,014
European (non-Finnish)	0.00178%	56,192
Finnishnot grpmax-eligible	0.00156%	64,038

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.Ala22Val
Coding: c.65C>T
MANE Select: NM_001374504
dbSNP: rs200558933
Type: single nucleotide variant
Location: chr22:37103353 (GRCh38)
Gene constraint: LOEUF 0.821 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 84.69 · 1 PDB

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.Ala22= Likely benign ★★ 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.Arg88Cys 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-ala22val (accessed [today's date]).

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