Is TRPM6 p.Gln1663Arg (c.4988A>G) pathogenic?

TRPM6 p.Gln1663Arg (c.4988A>G) is classified Benign/Likely benign in TRPM6 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0755); Low-frequency (popmax 1.95%, mid); Associated with intestinal hypomagnesemia 1.

What condition is associated with TRPM6 p.Gln1663Arg (c.4988A>G)?

TRPM6 p.Gln1663Arg (c.4988A>G) is associated with intestinal hypomagnesemia 1 (ClinVar).

How common is TRPM6 p.Gln1663Arg (c.4988A>G) in the general population?

TRPM6 p.Gln1663Arg (c.4988A>G) is low-frequency (popmax 1.95%, mid) (gnomAD).

What do computational predictors say about TRPM6 p.Gln1663Arg (c.4988A>G)?

AlphaMissense predicts likely benign (score 0.0755) — an in-silico prediction, not a clinical call.

TRPM6 p.Gln1663Arg

Q: How is Primary hypomagnesemia with secondary hypocalcemia inherited?

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

c.4988A>G · rs55679040 · VCV218740

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0755 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.95%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intestinal hypomagnesemia 1

Computational evidence

Protein change
AlphaMissense	0.0755	likely benign
REVEL	0.112	moderately benign-leaning
SaProt	LLR -5.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.5	GERP -0.38
Regional constraint	o/e 1.00	unconstrained · MANE · 28 kb · p 0.97 · regional, not allelic
Overall
CADD	14.41	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.95% Middle Eastern · 117/6,010 alleles

Filtering AF 1.66% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.55%

Overall 0.805% 12,773/1,586,390 alleles · low-frequency exomes 11,812/1,434,062 · genomes 961/152,328 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.95%	51
European (non-Finnish)	0.962%	104
Remaining individualsnot grpmax-eligible	0.745%	134
Admixed American	0.684%	146
Ashkenazi Jewishnot grpmax-eligible	0.364%	275
Finnishnot grpmax-eligible	0.363%	275
African / African-American	0.189%	529
South Asian	0.188%	532
Amishnot grpmax-eligible	0.11%	912
East Asian	0.00224%	44,686

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.Gln1663Arg
Coding: c.4988A>G
MANE Select: NM_017662
dbSNP: rs55679040
Type: single nucleotide variant
Location: chr9:74752287 (GRCh38)
Gene constraint: LOEUF 0.494 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 65.03
Residue 1663: a UniProt-annotated variant site (no effect on channel activity or cell membrane localization)

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

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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-gln1663arg (accessed [today's date]).

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