Is TMPRSS6 p.Pro546Ser (c.1636C>T) pathogenic?

TMPRSS6 p.Pro546Ser (c.1636C>T) is classified Benign in TMPRSS6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-14). AlphaMissense: likely benign (0.0812); Common (popmax 8.35%, sas) — too common for a highly-penetrant pathogenic allele; Associated with microcytic anemia.

What condition is associated with TMPRSS6 p.Pro546Ser (c.1636C>T)?

TMPRSS6 p.Pro546Ser (c.1636C>T) is associated with microcytic anemia (ClinVar).

What do computational predictors say about TMPRSS6 p.Pro546Ser (c.1636C>T)?

AlphaMissense predicts likely benign (score 0.0812) — an in-silico prediction, not a clinical call.

TMPRSS6 p.Pro546Ser

Q: How common is TMPRSS6 p.Pro546Ser (c.1636C>T) in the general population?

TMPRSS6 p.Pro546Ser (c.1636C>T) is common (popmax 8.35%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1636C>T · rs78174698 · VCV341582

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0812 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 8.35%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

microcytic anemia

Computational evidence

Protein change
AlphaMissense	0.0812	likely benign
REVEL	0.249	benign-leaning
SaProt	LLR -6.64	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 0.88	GERP -0.82
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.097 · regional, not allelic
Overall
CADD	1.598	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 P555S vs ClinVar P546S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.35% South Asian · 7,606/91,076 alleles

Filtering AF 8.19% ClinGen BA1/BS1 input FAF95, joint · FAF99 8.13%

Overall 0.592% 9,551/1,613,282 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	8.35%	12
African / African-American	1.53%	65
Remaining individualsnot grpmax-eligible	0.747%	134
Middle Eastern	0.479%	209
Admixed American	0.19%	526
East Asian	0.147%	680
European (non-Finnish)	0.0101%	9,916

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.Pro546Ser
Coding: c.1636C>T
MANE Select: NM_001374504
dbSNP: rs78174698
Type: single nucleotide variant
Location: chr22:37070952 (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 546: 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.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
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-pro546ser (accessed [today's date]).

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