Is TMPRSS6 p.Ala109Asp (c.326C>A) pathogenic?

TMPRSS6 p.Ala109Asp (c.326C>A) is classified Pathogenic in TMPRSS6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2009-10-01). AlphaMissense: likely pathogenic (0.8092); Very rare (popmax 0.000169%, nfe); Associated with IRIDA syndrome.

What condition is associated with TMPRSS6 p.Ala109Asp (c.326C>A)?

TMPRSS6 p.Ala109Asp (c.326C>A) is associated with IRIDA syndrome (ClinVar).

How common is TMPRSS6 p.Ala109Asp (c.326C>A) in the general population?

TMPRSS6 p.Ala109Asp (c.326C>A) is very rare (popmax 0.000169%, nfe) (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.Ala109Asp (c.326C>A)?

AlphaMissense predicts likely pathogenic (score 0.8092) — an in-silico prediction, not a clinical call.

TMPRSS6 p.Ala109Asp

c.326C>A · rs267607121 · VCV1410

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8092 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

IRIDA syndrome

Computational evidence

Protein change
AlphaMissense	0.8092	likely pathogenic ✓ concordant with ClinVar
REVEL	0.152	moderately benign-leaning
SaProt	LLR -9.88	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
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	26.0	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 A118D vs ClinVar A109D) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,998 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,876 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: TMPRSS6
Protein: p.Ala109Asp
Coding: c.326C>A
MANE Select: NM_001374504
dbSNP: rs267607121
Type: single nucleotide variant
Location: chr22:37098426 (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 109: the sea domain; an α-helix

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 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
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-ala109asp (accessed [today's date]).

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