Is TMPRSS6 p.Pro24= (c.72G>A) pathogenic?

TMPRSS6 p.Pro24= (c.72G>A) is classified Benign/Likely benign in TMPRSS6 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-02). Common (popmax 20.4%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with IRIDA syndrome.

What condition is associated with TMPRSS6 p.Pro24= (c.72G>A)?

TMPRSS6 p.Pro24= (c.72G>A) is associated with IRIDA syndrome, microcytic anemia (ClinVar).

How is IRIDA syndrome inherited?

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

TMPRSS6 p.Pro24=

Q: How common is TMPRSS6 p.Pro24= (c.72G>A) in the general population?

TMPRSS6 p.Pro24= (c.72G>A) is common (popmax 20.4%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.72G>A · rs11704654 · VCV262729

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 20.4%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

IRIDA syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -2.5
Overall
CADD	0.296	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 20.4% European (non-Finnish) · 240,570/1,179,984 alleles

Filtering AF 20.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 20.3%

Overall 18.9% 304,803/1,614,092 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	20.4%	5
European (non-Finnish)grpmax	20.4%	5
Ashkenazi Jewishnot grpmax-eligible	19.7%	5
Remaining individualsnot grpmax-eligible	18.2%	5
Finnishnot grpmax-eligible	15.7%	6
East Asian	15.3%	7
African / African-American	14.8%	7
Middle Eastern	14.4%	7
South Asian	12.6%	8
Admixed American	10.8%	9

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro24=
Coding: c.72G>A
MANE Select: NM_001374504
dbSNP: rs11704654
Type: single nucleotide variant
Location: chr22:37103346 (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

Also linked: microcytic anemia

For IRIDA syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TMPRSS6 p.Pro24Leu 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.Ala700Val 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-pro24 (accessed [today's date]).

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