Is TMPRSS6 p.Ser773= (c.2319C>T) pathogenic?

TMPRSS6 p.Ser773= (c.2319C>T) is classified Benign in TMPRSS6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-24). Common (popmax 5.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with microcytic anemia.

What condition is associated with TMPRSS6 p.Ser773= (c.2319C>T)?

TMPRSS6 p.Ser773= (c.2319C>T) is associated with microcytic anemia (ClinVar).

TMPRSS6 p.Ser773=

Q: How common is TMPRSS6 p.Ser773= (c.2319C>T) in the general population?

TMPRSS6 p.Ser773= (c.2319C>T) is common (popmax 5.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2319C>T · rs73886915 · VCV341577

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 5.7%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

microcytic anemia

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 7.5	GERP 2.3, phastCons 1
Overall
CADD	10.97	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.7% African / African-American · 4,279/75,052 alleles

Filtering AF 5.56% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.5%

Overall 0.306% 4,936/1,613,132 alleles · common exomes 2,423/1,460,808 · genomes 2,513/152,324 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.7%	18
Remaining individualsnot grpmax-eligible	0.418%	239
Admixed American	0.415%	241
Middle Eastern	0.182%	551
South Asian	0.011%	9,108
European (non-Finnish)	0.0107%	9,365

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.Ser773=
Coding: c.2319C>T
MANE Select: NM_001374504
dbSNP: rs73886915
Type: single nucleotide variant
Location: chr22:37066170 (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 773: the peptidase s1 domain

Full TMPRSS6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

microcytic anemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMPRSS6 p.Arg590Ter Pathogenic/Likely pathogenic ★★ same condition
TMPRSS6 p.Asp512Asn Likely pathogenic ★★ same condition
TMPRSS6 p.Ala700Val Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Arg43Cys Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Arg545Trp Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Arg735His Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Arg96His Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Glu151Lys 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-ser773 (accessed [today's date]).

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