Is TRPM6 p.Pro1808= (c.5424T>C) pathogenic?

TRPM6 p.Pro1808= (c.5424T>C) is classified Benign/Likely benign in TRPM6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-28). Rare (popmax 0.207%, afr); Associated with intestinal hypomagnesemia 1.

What condition is associated with TRPM6 p.Pro1808= (c.5424T>C)?

TRPM6 p.Pro1808= (c.5424T>C) is associated with intestinal hypomagnesemia 1 (ClinVar).

How common is TRPM6 p.Pro1808= (c.5424T>C) in the general population?

TRPM6 p.Pro1808= (c.5424T>C) is rare (popmax 0.207%, afr) (gnomAD).

TRPM6 p.Pro1808=

Q: How is Primary hypomagnesemia with secondary hypocalcemia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.5424T>C · rs140812450 · VCV792671

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.207%, afr)

Conditions

intestinal hypomagnesemia 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.64 · evaluated, not missing
Constraint at this position
Conservation	phyloP -3.8	GERP -3.9
Overall
CADD	3.475	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.207% African / African-American · 155/75,036 alleles

Filtering AF 0.18% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.17%

Overall 0.0104% 168/1,614,144 alleles · rare exomes 74/1,461,856 · genomes 94/152,288 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.207%	484
Remaining individualsnot grpmax-eligible	0.0144%	6,946
Admixed American	0.00667%	15,002

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: TRPM6
Protein: p.Pro1808=
Coding: c.5424T>C
MANE Select: NM_017662
dbSNP: rs140812450
Type: single nucleotide variant
Location: chr9:74739786 (GRCh38)
Gene constraint: LOEUF 0.494 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 65.03
Residue 1808: the alpha-type protein kinase domain

Full TRPM6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intestinal hypomagnesemia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Primary hypomagnesemia with secondary hypocalcemia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TRPM6 c.1308+7T>G Pathogenic ★★ same condition
TRPM6 c.841+1G>A Pathogenic ★★ same condition
TRPM6 p.Arg1772Ter Pathogenic ★★ same condition
TRPM6 p.Arg340Ter Pathogenic/Likely pathogenic ★★ same condition
TRPM6 p.Arg56Ter Pathogenic/Likely pathogenic ★★ same condition
TRPM6 p.Cys1429Ter Pathogenic/Likely pathogenic ★★ same condition
TRPM6 p.Gln1212Ter Likely pathogenic ★★ same condition
TRPM6 p.Tyr574Ter Pathogenic ★★ 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/trpm6-p-pro1808 (accessed [today's date]).

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