Is SLC22A5 p.Trp14Arg (c.40T>A) pathogenic?

SLC22A5 p.Trp14Arg (c.40T>A) is classified Pathogenic in SLC22A5 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-10-03). AlphaMissense: likely pathogenic (0.8963); Very rare (popmax 0.00017%, nfe); Associated with systemic primary carnitine deficiency disease.

What condition is associated with SLC22A5 p.Trp14Arg (c.40T>A)?

SLC22A5 p.Trp14Arg (c.40T>A) is associated with systemic primary carnitine deficiency disease (ClinVar).

How common is SLC22A5 p.Trp14Arg (c.40T>A) in the general population?

SLC22A5 p.Trp14Arg (c.40T>A) is very rare (popmax 0.00017%, nfe) (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.Trp14Arg (c.40T>A)?

AlphaMissense predicts likely pathogenic (score 0.8963) — an in-silico prediction, not a clinical call.

SLC22A5 p.Trp14Arg

c.40T>A · rs756863825 · VCV580421

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8963 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

systemic primary carnitine deficiency disease

Computational evidence

Protein change
AlphaMissense	0.8963	likely pathogenic ✓ concordant with ClinVar
REVEL	0.843	moderately pathogenic-leaning
SaProt	LLR -7.68	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 24 kb · p 0.074 · regional, not allelic
Overall
CADD	28.1	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 0.00017% European (non-Finnish) · 2/1,179,656 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,613,020 alleles · very rare exomes 4/1,460,916 · genomes 0/152,104 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,232
European (non-Finnish)grpmax	0.00017%	589,828

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Trp14Arg
Coding: c.40T>A
MANE Select: NM_003060
dbSNP: rs756863825
Type: single nucleotide variant
Location: chr5:132370012 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.45 · 3 PDB
Residue 14: 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 p.Trp14Ter Pathogenic/Likely pathogenic ★★ same residue
SLC22A5 p.Trp14Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-trp14arg (accessed [today's date]).

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