Is SLMAP p.Thr424Ile (c.1271C>T) pathogenic?

SLMAP p.Thr424Ile (c.1271C>T) is classified Uncertain significance in SLMAP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-11). AlphaMissense: ambiguous (0.3707); Very rare (popmax 0.00501%, amr); Associated with Brugada syndrome.

What condition is associated with SLMAP p.Thr424Ile (c.1271C>T)?

SLMAP p.Thr424Ile (c.1271C>T) is associated with Brugada syndrome (ClinVar).

How common is SLMAP p.Thr424Ile (c.1271C>T) in the general population?

SLMAP p.Thr424Ile (c.1271C>T) is very rare (popmax 0.00501%, amr) (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.Thr424Ile (c.1271C>T)?

AlphaMissense predicts ambiguous (score 0.3707) — an in-silico prediction, not a clinical call.

SLMAP p.Thr424Ile

c.1271C>T · rs1423544190 · VCV1362142

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3707 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Brugada syndrome

Computational evidence

Protein change
AlphaMissense	0.3707	ambiguous
REVEL	0.137	moderately benign-leaning
SaProt	LLR -8.22	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 2.4, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 94 kb · p 9.6e-06 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM T407I vs ClinVar T424I) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00501% Admixed American · 3/59,918 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000496% 8/1,612,420 alleles · very rare exomes 6/1,460,486 · genomes 2/151,934 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,973
Remaining individualsnot grpmax-eligible	0.0016%	62,440
European (non-Finnish)	0.000339%	294,739

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.Thr424Ile
Coding: c.1271C>T
MANE Select: NM_001377540
dbSNP: rs1423544190
Type: single nucleotide variant
Location: chr3:57871669 (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.Thr424Ala 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-thr424ile (accessed [today's date]).

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