Is SLC19A1 p.Leu338Phe (c.1012C>T) pathogenic?

SLC19A1 p.Leu338Phe (c.1012C>T) is classified Benign in SLC19A1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.1726); Low-frequency (popmax 1.53%, afr).

How common is SLC19A1 p.Leu338Phe (c.1012C>T) in the general population?

SLC19A1 p.Leu338Phe (c.1012C>T) is low-frequency (popmax 1.53%, afr) (gnomAD).

What do computational predictors say about SLC19A1 p.Leu338Phe (c.1012C>T)?

AlphaMissense predicts likely benign (score 0.1726) — an in-silico prediction, not a clinical call.

SLC19A1 p.Leu338Phe

c.1012C>T · rs59638403 · VCV724746

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1726 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.53%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1726	likely benign
REVEL	0.196	benign-leaning
SaProt	LLR -7.93	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 0.43	GERP -2.1, phastCons 0.99
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.89 · regional, not allelic
Overall
CADD	17.53	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 1.53% African / African-American · 1,031/67,588 alleles

Filtering AF 1.45% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.42%

Overall 0.0788% 1,163/1,476,568 alleles · low-frequency exomes 543/1,325,796 · genomes 620/150,772 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.53%	66
Admixed American	0.1%	999
Middle Eastern	0.0909%	1,100
Remaining individualsnot grpmax-eligible	0.087%	1,149
South Asian	0.00552%	18,125
European (non-Finnish)	0.00305%	32,827

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: SLC19A1
Protein: p.Leu338Phe
Coding: c.1012C>T
MANE Select: NM_194255
dbSNP: rs59638403
Type: single nucleotide variant
Location: chr21:45530909 (GRCh38)
Gene constraint: LOEUF 1.585 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.30 · 19 PDB
Residue 338: an α-helix

Full SLC19A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL18A1 p.Arg1081Ter Pathogenic/Likely pathogenic ★★ same type
COL18A1 p.Arg915Ter Pathogenic/Likely pathogenic ★★ same type
RFC1 p.Arg383Ter Pathogenic/Likely pathogenic ★★ same type
COL18A1 c.*30G>A Uncertain significance ★★ same type
COL18A1 p.Ala1089Thr Uncertain significance ★★ ⚠ same type
COL18A1 p.Ala1254Val Uncertain significance ★★ ⚠ same type
COL18A1 p.Arg1081Gln Uncertain significance ★★ ⚠ same type
COL18A1 p.Arg1183His Uncertain significance ★★ same type

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/slc19a1-p-leu338phe (accessed [today's date]).

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