Is TRPM6 p.Pro1978= (c.5934G>A) pathogenic?

TRPM6 p.Pro1978= (c.5934G>A) is classified Uncertain significance in TRPM6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-26). Ultra-rare (popmax 0.033%, sas); Associated with intestinal hypomagnesemia 1.

What condition is associated with TRPM6 p.Pro1978= (c.5934G>A)?

TRPM6 p.Pro1978= (c.5934G>A) is associated with intestinal hypomagnesemia 1 (ClinVar).

How common is TRPM6 p.Pro1978= (c.5934G>A) in the general population?

TRPM6 p.Pro1978= (c.5934G>A) is ultra-rare (popmax 0.033%, sas) (gnomAD).

TRPM6 p.Pro1978=

Q: How is Primary hypomagnesemia with secondary hypocalcemia inherited?

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

c.5934G>A · rs748626753 · VCV1901488

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, sas)

Conditions

intestinal hypomagnesemia 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.94	GERP -1.1
Overall
CADD	10.82	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% South Asian · 30/91,016 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.00366% 59/1,611,604 alleles · ultra-rare exomes 55/1,459,390 · genomes 4/152,214 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.033%	3,034
East Asian	0.00892%	11,212
European (non-Finnish)	0.00204%	49,074
Remaining individualsnot grpmax-eligible	0.0016%	62,432

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.Pro1978=
Coding: c.5934G>A
MANE Select: NM_017662
dbSNP: rs748626753
Type: single nucleotide variant
Location: chr9:74728240 (GRCh38)
Gene constraint: LOEUF 0.494 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 65.03
Residue 1978: 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 p.Pro1978Leu Uncertain significance ★★ ⚠ same residue
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

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-pro1978 (accessed [today's date]).

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