Is SLC22A5 p.Pro366Ser (c.1096C>T) pathogenic?

SLC22A5 p.Pro366Ser (c.1096C>T) is classified Uncertain significance in SLC22A5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely benign (0.2883); Very rare (popmax 0.00167%, amr); Associated with systemic primary carnitine deficiency disease.

What condition is associated with SLC22A5 p.Pro366Ser (c.1096C>T)?

SLC22A5 p.Pro366Ser (c.1096C>T) is associated with systemic primary carnitine deficiency disease (ClinVar).

How common is SLC22A5 p.Pro366Ser (c.1096C>T) in the general population?

SLC22A5 p.Pro366Ser (c.1096C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Systemic primary carnitine deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about SLC22A5 p.Pro366Ser (c.1096C>T)?

AlphaMissense predicts likely benign (score 0.2883) — an in-silico prediction, not a clinical call.

SLC22A5 p.Pro366Ser

c.1096C>T · rs767240544 · VCV1400850

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2883 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

systemic primary carnitine deficiency disease

Computational evidence

Protein change
AlphaMissense	0.2883	likely benign
REVEL	0.232	benign-leaning
SaProt	LLR -1.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 24 kb · p 0.074 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,020 alleles

Overall 0.000124% 2/1,614,232 alleles · very rare exomes 2/1,461,876 · genomes 0/152,356 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,020
European (non-Finnish)	8.47e-05%	1,180,038

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: SLC22A5
Protein: p.Pro366Ser
Coding: c.1096C>T
MANE Select: NM_003060
dbSNP: rs767240544
Type: single nucleotide variant
Location: chr5:132390733 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.45 · 3 PDB
Residue 366: a UniProt-annotated variant site (in cdsp)

Full SLC22A5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

systemic primary carnitine deficiency disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Systemic primary carnitine deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

SLC22A5 c.1053-2A>C Pathogenic/Likely pathogenic ★★ same condition
SLC22A5 c.1450+1G>A Likely pathogenic ★★ same condition
SLC22A5 c.1451-2A>G Pathogenic/Likely pathogenic ★★ same condition
SLC22A5 c.1586+1G>T Pathogenic/Likely pathogenic ★★ same condition
SLC22A5 c.393+1G>A Pathogenic/Likely pathogenic ★★ same condition
SLC22A5 c.394-1G>T Pathogenic/Likely pathogenic ★★ same condition
SLC22A5 c.394-2A>C Pathogenic/Likely pathogenic ★★ same condition
SLC22A5 c.497+1G>A Pathogenic/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/slc22a5-p-pro366ser (accessed [today's date]).

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