Is SLC19A3 p.Ser444Arg (c.1332C>G) pathogenic?

SLC19A3 p.Ser444Arg (c.1332C>G) is classified Pathogenic in SLC19A3 (ClinVar, Single submitter, 1 submitter; last evaluated 2014-04-16). AlphaMissense: likely pathogenic (0.8586); Very rare (popmax 0.00133%, afr).

How common is SLC19A3 p.Ser444Arg (c.1332C>G) in the general population?

SLC19A3 p.Ser444Arg (c.1332C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about SLC19A3 p.Ser444Arg (c.1332C>G)?

AlphaMissense predicts likely pathogenic (score 0.8586) — an in-silico prediction, not a clinical call.

SLC19A3 p.Ser444Arg

c.1332C>G · rs863224204 · VCV215158

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8586 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8586	likely pathogenic ✓ concordant with ClinVar · top 6% in SLC19A3
REVEL	0.718	pathogenic-leaning
SaProt	LLR -13.30	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Pangolin	Δ0.20	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 2.2	GERP -0.79, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 15 kb · p 0.85 · regional, not allelic
Overall
CADD	24.3	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 0.00133% African / African-American · 1/75,004 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,868 alleles · very rare exomes 4/1,461,688 · genomes 0/152,180 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,004
European (non-Finnish)	0.000254%	393,303

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.Ser444Arg
Coding: c.1332C>G
MANE Select: NM_025243
dbSNP: rs863224204
Type: single nucleotide variant
Location: chr2:227687556 (GRCh38)
Gene constraint: LOEUF 0.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.96 · 19 PDB
Residue 444: an α-helix

Full SLC19A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SLC19A3 c.1172+1G>A Pathogenic/Likely pathogenic ★★ same type
SLC19A3 c.1172+2T>G Pathogenic ★★ same type
SLC19A3 c.1173-1G>A Pathogenic/Likely pathogenic ★★ same type
SLC19A3 c.151-1G>C Likely pathogenic ★★ same type
SLC19A3 c.980-14A>G Pathogenic/Likely pathogenic ★★ same type
SLC19A3 p.Gly23Val Pathogenic/Likely pathogenic ★★ same type
SLC19A3 p.Met1Leu Likely pathogenic ★★ same type
SLC19A3 p.Ser181Pro Pathogenic ★★ 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/slc19a3-p-ser444arg (accessed [today's date]).

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