Is SLMAP p.Arg216Gln (c.647G>A) pathogenic?

SLMAP p.Arg216Gln (c.647G>A) is classified Uncertain significance in SLMAP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-16). AlphaMissense: likely pathogenic (0.7395); Very rare (popmax 0.00224%, eas); Associated with Brugada syndrome.

What condition is associated with SLMAP p.Arg216Gln (c.647G>A)?

SLMAP p.Arg216Gln (c.647G>A) is associated with Brugada syndrome (ClinVar).

How common is SLMAP p.Arg216Gln (c.647G>A) in the general population?

SLMAP p.Arg216Gln (c.647G>A) is very rare (popmax 0.00224%, eas) (gnomAD).

How is Brugada syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SLMAP p.Arg216Gln (c.647G>A)?

AlphaMissense predicts likely pathogenic (score 0.7395) — an in-silico prediction, not a clinical call.

SLMAP p.Arg216Gln

c.647G>A · VCV4738648

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7395 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Brugada syndrome

Computational evidence

Protein change
AlphaMissense	0.7395	likely pathogenic
REVEL	0.417	indeterminate
SaProt	LLR -9.53	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 94 kb · p 9.6e-06 · regional, not allelic
Overall
CADD	33.0	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 0.00224% East Asian · 1/44,694 alleles

Filtering AF 0.000366% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000624% 10/1,601,594 alleles · very rare exomes 10/1,449,486 · genomes 0/152,108 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,694
South Asian	0.0022%	45,370
Remaining individualsnot grpmax-eligible	0.00161%	62,062
European (non-Finnish)	0.000513%	194,833

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: SLMAP
Protein: p.Arg216Gln
Coding: c.647G>A
MANE Select: NM_001377540
Type: single nucleotide variant
Location: chr3:57858119 (GRCh38)
Gene constraint: LOEUF 0.531 · pLI 0.86 (gnomAD)
Structure: AlphaFold pLDDT 77.74 · 3 PDB

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

Disease context

Brugada syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Brugada syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

SLMAP p.Arg216Trp Uncertain significance ★★ ⚠ same residue
SLMAP c.*38C>T Uncertain significance ★★ ⚠ same condition
SLMAP c.*55G>A Uncertain significance ★★ ⚠ same condition
SLMAP c.*70G>A Uncertain significance ★★ ⚠ same condition
SLMAP p.Ala365Asp Uncertain significance ★★ ⚠ same condition
SLMAP p.Ala506Ser Uncertain significance ★★ ⚠ same condition
SLMAP p.Ala597Val Uncertain significance ★★ ⚠ same condition
SLMAP p.Arg136Gln Uncertain significance ★★ ⚠ 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/slmap-p-arg216gln (accessed [today's date]).

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