Is TMPRSS6 p.Arg545Gln (c.1634G>A) pathogenic?

TMPRSS6 p.Arg545Gln (c.1634G>A) is classified Benign/Likely benign in TMPRSS6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-18). AlphaMissense: likely benign (0.0564); Low-frequency (popmax 1.04%, sas); Associated with microcytic anemia.

What condition is associated with TMPRSS6 p.Arg545Gln (c.1634G>A)?

TMPRSS6 p.Arg545Gln (c.1634G>A) is associated with microcytic anemia (ClinVar).

How common is TMPRSS6 p.Arg545Gln (c.1634G>A) in the general population?

TMPRSS6 p.Arg545Gln (c.1634G>A) is low-frequency (popmax 1.04%, sas) (gnomAD).

What do computational predictors say about TMPRSS6 p.Arg545Gln (c.1634G>A)?

AlphaMissense predicts likely benign (score 0.0564) — an in-silico prediction, not a clinical call.

TMPRSS6 p.Arg545Gln

c.1634G>A · rs150953057 · VCV903103

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0564 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.04%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcytic anemia

Computational evidence

Protein change
AlphaMissense	0.0564	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -5.74	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.7	GERP -3.5
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.097 · regional, not allelic
Overall
CADD	0.017	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 R554Q vs ClinVar R545Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.04% South Asian · 943/91,080 alleles

Filtering AF 0.98% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.959%

Overall 0.0666% 1,074/1,613,358 alleles · low-frequency

Ancestry group	Frequency	1 in
South Asiangrpmax	1.04%	97
Remaining individualsnot grpmax-eligible	0.08%	1,250
African / African-American	0.0413%	2,420
Middle Eastern	0.033%	3,028
Admixed American	0.01%	10,003
European (non-Finnish)	0.00356%	28,095

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.Arg545Gln
Coding: c.1634G>A
MANE Select: NM_001374504
dbSNP: rs150953057
Type: single nucleotide variant
Location: chr22:37070954 (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 545: a β-strand; a disulfide bond; the ldl-receptor class a 3 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.Arg545Trp 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.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-arg545gln (accessed [today's date]).

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