Is SLC6A9 p.Val431Met (c.1291G>A) pathogenic?

SLC6A9 p.Val431Met (c.1291G>A) is classified Uncertain significance in SLC6A9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: likely benign (0.1487); Ultra-rare (popmax 0.0254%, afr); Associated with Inborn genetic diseases.

What condition is associated with SLC6A9 p.Val431Met (c.1291G>A)?

SLC6A9 p.Val431Met (c.1291G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SLC6A9 p.Val431Met (c.1291G>A) in the general population?

SLC6A9 p.Val431Met (c.1291G>A) is ultra-rare (popmax 0.0254%, afr) (gnomAD).

What do computational predictors say about SLC6A9 p.Val431Met (c.1291G>A)?

AlphaMissense predicts likely benign (score 0.1487) — an in-silico prediction, not a clinical call.

SLC6A9 p.Val431Met

c.1291G>A · VCV4169077

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1487 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0254%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1487	likely benign
REVEL	0.516	indeterminate
SaProt	LLR -9.68	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 27 kb · p 1.8e-13 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V504M vs ClinVar V431M) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0254% African / African-American · 19/74,942 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00204% 33/1,614,130 alleles · ultra-rare exomes 19/1,461,894 · genomes 14/152,236 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0254%	3,944
Remaining individualsnot grpmax-eligible	0.0032%	31,245
Admixed American	0.00167%	60,010
South Asian	0.0011%	91,090
European (non-Finnish)	0.000847%	118,005

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: SLC6A9
Protein: p.Val431Met
Coding: c.1291G>A
MANE Select: NM_001024845
Type: single nucleotide variant
Location: chr1:44001208 (GRCh38)
Gene constraint: LOEUF 0.544 · pLI 0.51 (gnomAD)
Structure: AlphaFold pLDDT 81.95 · 9 PDB
Residue 504 UniProt numbering: an α-helix

Full SLC6A9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SLC6A9 p.Ala538Val Uncertain significance ★★ ⚠ same condition
SLC6A9 p.Arg570His Uncertain significance ★★ ⚠ same condition
SLC6A9 p.Arg627His Uncertain significance ★★ ⚠ same condition
SLC6A9 p.Pro524Leu Uncertain significance ★★ ⚠ same condition
SLC6A9 p.Ser179Pro Uncertain significance ★★ ⚠ same condition
SLC6A9 p.Thr153Met Uncertain significance ★★ same condition
SLC6A9 p.Thr248Met Uncertain significance ★★ ⚠ same condition
SLC6A9 p.Val98Phe 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/slc6a9-p-val431met (accessed [today's date]).

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