Is TMPRSS6 p.Arg601His (c.1802G>A) pathogenic?

TMPRSS6 p.Arg601His (c.1802G>A) is classified Uncertain significance in TMPRSS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-13). AlphaMissense: likely benign (0.0936); Rare (popmax 0.149%, afr).

How common is TMPRSS6 p.Arg601His (c.1802G>A) in the general population?

TMPRSS6 p.Arg601His (c.1802G>A) is rare (popmax 0.149%, afr) (gnomAD).

What do computational predictors say about TMPRSS6 p.Arg601His (c.1802G>A)?

AlphaMissense predicts likely benign (score 0.0936) — an in-silico prediction, not a clinical call.

TMPRSS6 p.Arg601His

c.1802G>A · VCV3380715

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0936 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.149%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0936	likely benign
REVEL	0.55	indeterminate
SaProt	LLR -8.85	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 0.72, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.097 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R610H vs ClinVar R601H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.149% African / African-American · 112/75,056 alleles

Filtering AF 0.127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.118%

Overall 0.00843% 136/1,613,444 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.149%	670
Admixed American	0.0183%	5,457
Remaining individualsnot grpmax-eligible	0.0064%	15,624
East Asian	0.00446%	22,437
South Asian	0.0022%	45,542
European (non-Finnish)	0.000424%	236,004

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.Arg601His
Coding: c.1802G>A
MANE Select: NM_001374504
Type: single nucleotide variant
Location: chr22:37070523 (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 601: the peptidase s1 domain; a β-strand

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

Similar variants

TMPRSS6 p.Arg601Cys Uncertain significance ★ ⚠ same residue
TMPRSS6 p.Arg601= Likely benign ★ same residue
TMPRSS6 c.1342+1G>A Pathogenic/Likely pathogenic ★★ same type
TMPRSS6 p.Arg590Ter Pathogenic/Likely pathogenic ★★ same type
TMPRSS6 p.Asp512Asn Likely pathogenic ★★ same type
TMPRSS6 p.Gly433Arg Pathogenic/Likely pathogenic ★★ ⚠ same type
TMPRSS6 p.Lys70Ter Likely pathogenic ★★ same type
TMPRSS6 p.Ser552Ter Pathogenic ★★ same type

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-arg601his (accessed [today's date]).

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