Is TMPRSS6 p.Ser446Trp (c.1337C>G) pathogenic?

TMPRSS6 p.Ser446Trp (c.1337C>G) is classified Uncertain significance in TMPRSS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-01). AlphaMissense: ambiguous (0.5141); Rare (popmax 0.104%, afr); Associated with Inborn genetic diseases.

What condition is associated with TMPRSS6 p.Ser446Trp (c.1337C>G)?

TMPRSS6 p.Ser446Trp (c.1337C>G) is associated with Inborn genetic diseases (ClinVar).

How common is TMPRSS6 p.Ser446Trp (c.1337C>G) in the general population?

TMPRSS6 p.Ser446Trp (c.1337C>G) is rare (popmax 0.104%, afr) (gnomAD).

What do computational predictors say about TMPRSS6 p.Ser446Trp (c.1337C>G)?

AlphaMissense predicts ambiguous (score 0.5141) — an in-silico prediction, not a clinical call.

TMPRSS6 p.Ser446Trp

c.1337C>G · VCV3327356

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5141 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.104%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5141	ambiguous
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -11.46	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.097 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S455W vs ClinVar S446W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.104% African / African-American · 78/75,066 alleles

Filtering AF 0.0853% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0785%

Overall 0.00514% 83/1,613,742 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.104%	962
Admixed American	0.00333%	30,017
Remaining individualsnot grpmax-eligible	0.0032%	31,255
European (non-Finnish)	8.47e-05%	1,180,038

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.Ser446Trp
Coding: c.1337C>G
MANE Select: NM_001374504
Type: single nucleotide variant
Location: chr22:37075140 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TMPRSS6 p.Ser446= Uncertain significance ★ same residue
TMPRSS6 p.Ala164Thr Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Ala700Val Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Arg121His Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Arg251Gln Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Arg545Trp Uncertain significance ★★ ⚠ same condition
TMPRSS6 p.Arg780Gln 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-ser446trp (accessed [today's date]).

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