Is SLC19A1 p.Phe103Leu (c.309C>G) pathogenic?

SLC19A1 p.Phe103Leu (c.309C>G) is classified Uncertain significance in SLC19A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-14). AlphaMissense: likely pathogenic (0.7698); Ultra-rare (popmax 0.01%, amr).

How common is SLC19A1 p.Phe103Leu (c.309C>G) in the general population?

SLC19A1 p.Phe103Leu (c.309C>G) is ultra-rare (popmax 0.01%, amr) (gnomAD).

What do computational predictors say about SLC19A1 p.Phe103Leu (c.309C>G)?

AlphaMissense predicts likely pathogenic (score 0.7698) — an in-silico prediction, not a clinical call.

SLC19A1 p.Phe103Leu

c.309C>G · VCV4584680

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7698 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7698	likely pathogenic
REVEL	0.294	indeterminate
SaProt	LLR -4.35	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.18	GERP -1.9
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.89 · regional, not allelic
Overall
CADD	13.36	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 · 6/59,990 alleles

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

Overall 0.000496% 8/1,611,880 alleles · ultra-rare exomes 8/1,459,540 · genomes 0/152,340 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	9,998
Remaining individualsnot grpmax-eligible	0.0016%	62,466
European (non-Finnish)	8.48e-05%	1,179,885

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.Phe103Leu
Coding: c.309C>G
MANE Select: NM_194255
Type: single nucleotide variant
Location: chr21:45532029 (GRCh38)
Gene constraint: LOEUF 1.585 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.30 · 19 PDB
Residue 103: 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-phe103leu (accessed [today's date]).

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