Is SLC19A3 p.Ser457Asn (c.1370G>A) pathogenic?

SLC19A3 p.Ser457Asn (c.1370G>A) is classified Conflicting classifications of pathogenicity in SLC19A3 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-25). AlphaMissense: likely benign (0.2602); Ultra-rare (popmax 0.0283%, amr); Associated with Inborn genetic diseases.

What condition is associated with SLC19A3 p.Ser457Asn (c.1370G>A)?

SLC19A3 p.Ser457Asn (c.1370G>A) is associated with Inborn genetic diseases, biotin-responsive basal ganglia disease (ClinVar).

How common is SLC19A3 p.Ser457Asn (c.1370G>A) in the general population?

SLC19A3 p.Ser457Asn (c.1370G>A) is ultra-rare (popmax 0.0283%, amr) (gnomAD).

What do computational predictors say about SLC19A3 p.Ser457Asn (c.1370G>A)?

AlphaMissense predicts likely benign (score 0.2602) — an in-silico prediction, not a clinical call.

SLC19A3 p.Ser457Asn

c.1370G>A · rs138839321 · VCV464952

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2602 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0283%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2602	likely benign
REVEL	0.483	indeterminate
SaProt	LLR -7.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 15 kb · p 0.85 · regional, not allelic
Overall
CADD	24.2	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 0.0283% Admixed American · 17/60,014 alleles

Filtering AF 0.018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.0188% 304/1,614,076 alleles · ultra-rare exomes 270/1,461,798 · genomes 34/152,278 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.706%	142
Remaining individualsnot grpmax-eligible	0.0576%	1,736
Admixed Americangrpmax	0.0283%	3,530
East Asian	0.0134%	7,478
European (non-Finnish)	0.00297%	33,714
African / African-American	0.00133%	75,046

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SLC19A3
Protein: p.Ser457Asn
Coding: c.1370G>A
MANE Select: NM_025243
dbSNP: rs138839321
Type: single nucleotide variant
Location: chr2:227687518 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB

Full SLC19A3 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: biotin-responsive basal ganglia disease

Similar variants

SLC19A3 p.Ser457Lys Uncertain significance ★ same residue
SLC19A3 c.1172+1G>A Pathogenic/Likely pathogenic ★★ same condition
SLC19A3 c.1172+2T>G Pathogenic ★★ same condition
SLC19A3 c.1173-1G>A Pathogenic/Likely pathogenic ★★ same condition
SLC19A3 c.151-1G>C Likely pathogenic ★★ same condition
SLC19A3 c.980-14A>G Pathogenic/Likely pathogenic ★★ same condition
SLC19A3 p.Gly23Val Pathogenic/Likely pathogenic ★★ same condition
SLC19A3 p.Met1Leu 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/slc19a3-p-ser457asn (accessed [today's date]).

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