Is SLC6A19 p.Val125Met (c.373G>A) pathogenic?

SLC6A19 p.Val125Met (c.373G>A) is classified Uncertain significance in SLC6A19 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-24). AlphaMissense: likely benign (0.325); Very rare (popmax 0.00661%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SLC6A19 p.Val125Met (c.373G>A)?

SLC6A19 p.Val125Met (c.373G>A) is associated with Inborn genetic diseases, Hartnup disease (ClinVar).

How common is SLC6A19 p.Val125Met (c.373G>A) in the general population?

SLC6A19 p.Val125Met (c.373G>A) is very rare (popmax 0.00661%, nfe) (gnomAD).

What do computational predictors say about SLC6A19 p.Val125Met (c.373G>A)?

AlphaMissense predicts likely benign (score 0.325) — an in-silico prediction, not a clinical call.

SLC6A19 p.Val125Met

c.373G>A · rs766877452 · VCV2222723

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.325 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00661%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.325	likely benign
REVEL	0.72	pathogenic-leaning
SaProt	LLR -9.08	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 20 kb · p 0.19 · regional, not allelic
Overall
CADD	24.6	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 0.00661% European (non-Finnish) · 78/1,180,046 alleles

Filtering AF 0.00538% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00498%

Overall 0.00521% 84/1,613,270 alleles · very rare exomes 77/1,461,014 · genomes 7/152,256 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00661%	15,129
Finnishnot grpmax-eligible	0.00475%	21,067
African / African-American	0.004%	24,981

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: SLC6A19
Protein: p.Val125Met
Coding: c.373G>A
MANE Select: NM_001003841
dbSNP: rs766877452
Type: single nucleotide variant
Location: chr5:1210473 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.20 · 21 PDB
Residue 125: an α-helix

Full SLC6A19 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

Also linked: Hartnup disease

Similar variants

SLC6A19 p.Val125Leu Uncertain significance ★ ⚠ same residue
SLC6A19 c.1173+2T>C Pathogenic/Likely pathogenic ★★ same condition
SLC6A19 c.1173+2T>G Pathogenic ★★ same condition
SLC6A19 p.Arg178Ter Pathogenic/Likely pathogenic ★★ same condition
SLC6A19 p.Arg240Ter Pathogenic ★★ same condition
SLC6A19 p.Asp173Asn Pathogenic/Likely pathogenic ★★ ⚠ same condition
SLC6A19 p.Asp517Gly Likely pathogenic ★★ same condition
SLC6A19 p.Glu501Lys Pathogenic/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/slc6a19-p-val125met (accessed [today's date]).

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