Is SLC13A5 p.Val431Met (c.1291G>A) pathogenic?

SLC13A5 p.Val431Met (c.1291G>A) is classified Conflicting classifications of pathogenicity in SLC13A5 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-13). AlphaMissense: likely benign (0.0885); Rare (popmax 0.154%, eas); Associated with developmental and epileptic encephalopathy, 25.

What condition is associated with SLC13A5 p.Val431Met (c.1291G>A)?

SLC13A5 p.Val431Met (c.1291G>A) is associated with developmental and epileptic encephalopathy, 25 (ClinVar).

How common is SLC13A5 p.Val431Met (c.1291G>A) in the general population?

SLC13A5 p.Val431Met (c.1291G>A) is rare (popmax 0.154%, eas) (gnomAD).

What do computational predictors say about SLC13A5 p.Val431Met (c.1291G>A)?

AlphaMissense predicts likely benign (score 0.0885) — an in-silico prediction, not a clinical call.

SLC13A5 p.Val431Met

Q: How is Non-specific early-onset epileptic encephalopathy inherited?

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

c.1291G>A · rs201036096 · VCV475192

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0885 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.154%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 25

Computational evidence

Protein change
AlphaMissense	0.0885	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -7.42	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 1.8	GERP 0.85, phastCons 0.91
Regional constraint	o/e 0.88	unconstrained · MANE · 27 kb · p 0.0011 · regional, not allelic
Overall
CADD	21.2	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 0.154% East Asian · 69/44,830 alleles

Filtering AF 0.125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.114%

Overall 0.00596% 96/1,609,696 alleles · rare exomes 79/1,457,372 · genomes 17/152,324 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.154%	650
Remaining individualsnot grpmax-eligible	0.0112%	8,905
African / African-American	0.008%	12,506
Finnishnot grpmax-eligible	0.00784%	12,759
South Asian	0.00111%	90,366
European (non-Finnish)	0.000679%	147,167

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: SLC13A5
Protein: p.Val431Met
Coding: c.1291G>A
MANE Select: NM_177550
dbSNP: rs201036096
Type: single nucleotide variant
Location: chr17:6690925 (GRCh38)
Gene constraint: LOEUF 0.549 · pLI 0.70 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.97 · 7 PDB
Residue 431: a UniProt-annotated variant site (in dee25; loss of localization to plasma membrane; loss of function in citrate transport); an α-helix

Full SLC13A5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 25 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-specific early-onset epileptic encephalopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Infancy, Neonatal

Similar variants

SLC13A5 p.Val431Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
SLC13A5 p.Val431= Likely benign ★ same residue
SLC13A5 c.1276-1G>A Pathogenic/Likely pathogenic ★★ same condition
SLC13A5 c.548-1G>A Likely pathogenic ★★ same condition
SLC13A5 c.548-2A>G Likely pathogenic ★★ same condition
SLC13A5 p.Arg333Ter Pathogenic/Likely pathogenic ★★ same condition
SLC13A5 p.Gly219Arg Pathogenic/Likely pathogenic ★★ same condition
SLC13A5 p.Leu488Pro 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/slc13a5-p-val431met (accessed [today's date]).

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