Is TMPRSS6 p.Pro540Gln (c.1619C>A) pathogenic?

TMPRSS6 p.Pro540Gln (c.1619C>A) is classified Uncertain significance in TMPRSS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-07-20). AlphaMissense: likely pathogenic (0.6935); Absent from gnomAD v4.1.

How common is TMPRSS6 p.Pro540Gln (c.1619C>A) in the general population?

TMPRSS6 p.Pro540Gln (c.1619C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TMPRSS6 p.Pro540Gln (c.1619C>A)?

AlphaMissense predicts likely pathogenic (score 0.6935) — an in-silico prediction, not a clinical call.

TMPRSS6 p.Pro540Gln

c.1619C>A · rs201244227 · VCV450615

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6935 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6935	likely pathogenic
REVEL	0.651	pathogenic-leaning
SaProt	LLR -10.52	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 P549Q vs ClinVar P540Q) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TMPRSS6
Protein: p.Pro540Gln
Coding: c.1619C>A
MANE Select: NM_001374504
dbSNP: rs201244227
Type: single nucleotide variant
Location: chr22:37070969 (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 540: a disulfide bond; the ldl-receptor class a 3 domain

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

Similar variants

TMPRSS6 p.Pro540Leu Uncertain significance ★ same residue
TMPRSS6 p.Pro540= 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-pro540gln (accessed [today's date]).

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