Is TMPRSS6 p.Ser446= (c.1338G>A) pathogenic?

TMPRSS6 p.Ser446= (c.1338G>A) is classified Uncertain significance in TMPRSS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Ultra-rare (popmax 0.0178%, eas); Associated with microcytic anemia.

What condition is associated with TMPRSS6 p.Ser446= (c.1338G>A)?

TMPRSS6 p.Ser446= (c.1338G>A) is associated with microcytic anemia (ClinVar).

How common is TMPRSS6 p.Ser446= (c.1338G>A) in the general population?

TMPRSS6 p.Ser446= (c.1338G>A) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

TMPRSS6 p.Ser446=

c.1338G>A · rs776737568 · VCV341587

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

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 -8.8	GERP -3.7
Overall
CADD	5.626	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0178% East Asian · 8/44,888 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00483% 78/1,613,630 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,611
Admixed American	0.0167%	6,001
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)	0.00458%	21,853
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
South Asian	0.0022%	45,543

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.Ser446=
Coding: c.1338G>A
MANE Select: NM_001374504
dbSNP: rs776737568
Type: single nucleotide variant
Location: chr22:37075139 (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 446: a β-strand; a UniProt-annotated variant site (in); the cub 2 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.Ser446Trp Uncertain significance ★ ⚠ same residue
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

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-ser446 (accessed [today's date]).

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