Is TMPRSS6 p.Glu136Lys (c.406G>A) pathogenic?

TMPRSS6 p.Glu136Lys (c.406G>A) is classified Conflicting classifications of pathogenicity in TMPRSS6 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-27). AlphaMissense: likely benign (0.1207); Rare (popmax 0.76%, afr); Associated with TMPRSS6-related disorder.

What condition is associated with TMPRSS6 p.Glu136Lys (c.406G>A)?

TMPRSS6 p.Glu136Lys (c.406G>A) is associated with TMPRSS6-related disorder, microcytic anemia (ClinVar).

How common is TMPRSS6 p.Glu136Lys (c.406G>A) in the general population?

TMPRSS6 p.Glu136Lys (c.406G>A) is rare (popmax 0.76%, afr) (gnomAD).

What do computational predictors say about TMPRSS6 p.Glu136Lys (c.406G>A)?

AlphaMissense predicts likely benign (score 0.1207) — an in-silico prediction, not a clinical call.

TMPRSS6 p.Glu136Lys

c.406G>A · rs116310349 · VCV899546

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1207 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.76%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TMPRSS6-related disorder

Computational evidence

Protein change
AlphaMissense	0.1207	likely benign
REVEL	0.284	benign-leaning
SaProt	LLR -6.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 0.42, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.097 · regional, not allelic
Overall
CADD	24.6	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 E145K vs ClinVar E136K) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.76% African / African-American · 570/75,046 alleles

Filtering AF 0.708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.687%

Overall 0.0379% 612/1,614,114 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.76%	132
Remaining individualsnot grpmax-eligible	0.0368%	2,718
Admixed American	0.0217%	4,617
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.000424%	236,005

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.Glu136Lys
Coding: c.406G>A
MANE Select: NM_001374504
dbSNP: rs116310349
Type: single nucleotide variant
Location: chr22:37096089 (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 136: the sea domain; a β-strand

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

Disease context

TMPRSS6-related disorder

Also linked: microcytic anemia

Similar variants

TMPRSS6 p.Arg590Ter Pathogenic/Likely pathogenic ★★ same condition
TMPRSS6 p.Asp512Asn Likely pathogenic ★★ same condition
TMPRSS6 p.Lys70Ter Likely pathogenic ★★ same condition
TMPRSS6 p.Ser552Ter Pathogenic ★★ same condition
TMPRSS6 p.Tyr346Ter 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

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-glu136lys (accessed [today's date]).

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