Is SLC19A3 p.Pro81Leu (c.242C>T) pathogenic?

SLC19A3 p.Pro81Leu (c.242C>T) is classified Uncertain significance in SLC19A3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-06). AlphaMissense: likely benign (0.2808); Ultra-rare (popmax 0.01%, amr); Associated with Inborn genetic diseases.

What condition is associated with SLC19A3 p.Pro81Leu (c.242C>T)?

SLC19A3 p.Pro81Leu (c.242C>T) is associated with Inborn genetic diseases, biotin-responsive basal ganglia disease (ClinVar).

How common is SLC19A3 p.Pro81Leu (c.242C>T) in the general population?

SLC19A3 p.Pro81Leu (c.242C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about SLC19A3 p.Pro81Leu (c.242C>T)?

AlphaMissense predicts likely benign (score 0.2808) — an in-silico prediction, not a clinical call.

SLC19A3 p.Pro81Leu

c.242C>T · rs752029795 · VCV660861

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2808 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2808	likely benign
REVEL	0.818	moderately pathogenic-leaning
SaProt	LLR -12.74	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.89, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 15 kb · p 0.85 · regional, not allelic
Overall
CADD	28.7	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 0.01% Admixed American · 6/59,988 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.000496% 8/1,614,054 alleles · ultra-rare exomes 7/1,461,894 · genomes 1/152,160 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,998
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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.Pro81Leu
Coding: c.242C>T
MANE Select: NM_025243
dbSNP: rs752029795
Type: single nucleotide variant
Location: chr2:227699473 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB
Residue 81: an α-helix

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.Pro81= Likely benign ★ 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-pro81leu (accessed [today's date]).

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