Is TRPM6 p.Arg549= (c.1647A>G) pathogenic?

TRPM6 p.Arg549= (c.1647A>G) is classified Conflicting classifications of pathogenicity in TRPM6 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-11). Ultra-rare (popmax 0.035%, amr); Associated with intestinal hypomagnesemia 1.

What condition is associated with TRPM6 p.Arg549= (c.1647A>G)?

TRPM6 p.Arg549= (c.1647A>G) is associated with intestinal hypomagnesemia 1 (ClinVar).

How common is TRPM6 p.Arg549= (c.1647A>G) in the general population?

TRPM6 p.Arg549= (c.1647A>G) is ultra-rare (popmax 0.035%, amr) (gnomAD).

TRPM6 p.Arg549=

Q: How is Primary hypomagnesemia with secondary hypocalcemia inherited?

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

c.1647A>G · rs148657084 · VCV367321

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

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 -0.54, phastCons 0.004
Overall
CADD	2.71	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.035% Admixed American · 21/60,006 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.0132% 213/1,610,666 alleles · ultra-rare exomes 185/1,458,428 · genomes 28/152,238 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.035%	2,857
European (non-Finnish)	0.0153%	6,538
Remaining individualsnot grpmax-eligible	0.0112%	8,913
Finnishnot grpmax-eligible	0.00625%	16,002
African / African-American	0.00133%	74,946

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.Arg549=
Coding: c.1647A>G
MANE Select: NM_017662
dbSNP: rs148657084
Type: single nucleotide variant
Location: chr9:74803878 (GRCh38)
Gene constraint: LOEUF 0.494 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 65.03

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-arg549 (accessed [today's date]).

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