Is TMPRSS6 p.Met615fs (c.1842_1843insCCACC) pathogenic?

TMPRSS6 p.Met615fs (c.18421843insCCACC) is classified Uncertain significance in TMPRSS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-02). Ultra-rare (popmax 0.0807%, afr); Associated with IRIDA syndrome.

What condition is associated with TMPRSS6 p.Met615fs (c.1842_1843insCCACC)?

TMPRSS6 p.Met615fs (c.1842_1843insCCACC) is associated with IRIDA syndrome (ClinVar).

How common is TMPRSS6 p.Met615fs (c.1842_1843insCCACC) in the general population?

TMPRSS6 p.Met615fs (c.1842_1843insCCACC) is ultra-rare (popmax 0.0807%, afr) (gnomAD).

How is IRIDA syndrome inherited?

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

TMPRSS6 p.Met615fs

c.1842_1843insCCACC · rs1416004303 · VCV2500890

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0807%, afr)

Conditions

IRIDA syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 16 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 0.9, phastCons 1
Overall
CADD	34.0	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

Grpmax group 0.0807% African / African-American · 10/12,386 alleles

Filtering AF 0.0438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0333%

Overall 0.00412% 10/242,800 alleles · ultra-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.Met615fs
Coding: c.1842_1843insCCACC
MANE Select: NM_001374504
dbSNP: rs1416004303
Type: Insertion
Location: chr22:37069343 (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 615: the peptidase s1 domain; a disulfide bond

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-met615fs (accessed [today's date]).

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