Is TMPRSS6 p.Ser352Ter (c.1055C>A) pathogenic?

TMPRSS6 p.Ser352Ter (c.1055C>A) is classified Pathogenic in TMPRSS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-25). Absent from gnomAD v4.1; Associated with IRIDA syndrome.

What condition is associated with TMPRSS6 p.Ser352Ter (c.1055C>A)?

TMPRSS6 p.Ser352Ter (c.1055C>A) is associated with IRIDA syndrome (ClinVar).

How common is TMPRSS6 p.Ser352Ter (c.1055C>A) in the general population?

TMPRSS6 p.Ser352Ter (c.1055C>A) is absent from gnomAD v4.1 (gnomAD).

How is IRIDA syndrome inherited?

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

TMPRSS6 p.Ser352Ter

c.1055C>A · rs776912815 · VCV2412690

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,566,432)

Conditions

IRIDA syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 18
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,566,432). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TMPRSS6
Protein: p.Ser352Ter
Coding: c.1055C>A
MANE Select: NM_001374504
dbSNP: rs776912815
Type: single nucleotide variant
Location: chr22:37084758 (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 352: a β-strand; a disulfide bond; the cub 2 domain

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.Ser352= Benign/Likely benign ★★ same residue
TMPRSS6 p.Ser352Leu 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

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-ser352ter (accessed [today's date]).

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