Is TMPRSS6 p.Pro271Ser (c.811C>T) pathogenic?

TMPRSS6 p.Pro271Ser (c.811C>T) is classified Uncertain significance in TMPRSS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-30). AlphaMissense: likely pathogenic (0.7182); Very rare (popmax 0.00134%, afr).

How common is TMPRSS6 p.Pro271Ser (c.811C>T) in the general population?

TMPRSS6 p.Pro271Ser (c.811C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about TMPRSS6 p.Pro271Ser (c.811C>T)?

AlphaMissense predicts likely pathogenic (score 0.7182) — an in-silico prediction, not a clinical call.

TMPRSS6 p.Pro271Ser

c.811C>T · VCV3693374

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7182 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7182	likely pathogenic
REVEL	0.482	indeterminate
SaProt	LLR -7.44	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 37 kb · p 0.097 · regional, not allelic
Overall
CADD	25.4	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 P280S vs ClinVar P271S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,810 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,611,832 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,810
European (non-Finnish)	0.00017%	589,723

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.Pro271Ser
Coding: c.811C>T
MANE Select: NM_001374504
Type: single nucleotide variant
Location: chr22:37089603 (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 271: the cub 1 domain; a UniProt-annotated variant site (in irida; no effect on hjv-mediated inhibition of hamp transcription; no effect on localization to the cell membrane; no effect on catalytic activity; hjv processing is not affected); a β-strand

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

Similar variants

TMPRSS6 p.Pro271His Uncertain significance ★ ⚠ 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
TMPRSS6 p.Tyr346Ter Likely 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-pro271ser (accessed [today's date]).

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