Is SLC5A2 p.Ser396Phe (c.1187C>T) pathogenic?

SLC5A2 p.Ser396Phe (c.1187C>T) is classified Uncertain significance in SLC5A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-10). AlphaMissense: likely pathogenic (0.9962); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SLC5A2 p.Ser396Phe (c.1187C>T)?

SLC5A2 p.Ser396Phe (c.1187C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SLC5A2 p.Ser396Phe (c.1187C>T) in the general population?

SLC5A2 p.Ser396Phe (c.1187C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about SLC5A2 p.Ser396Phe (c.1187C>T)?

AlphaMissense predicts likely pathogenic (score 0.9962) — an in-silico prediction, not a clinical call.

SLC5A2 p.Ser396Phe

c.1187C>T · VCV4631452

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9962 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9962	likely pathogenic · top 2% in SLC5A2
REVEL	0.89	moderately pathogenic-leaning
SaProt	LLR -16.54	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.86, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 7,395 bp · p 0.0088 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.48e-05% European (non-Finnish) · 1/1,179,594 alleles

Overall 6.85e-05% 1/1,460,366 alleles · very rare

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: SLC5A2
Protein: p.Ser396Phe
Coding: c.1187C>T
MANE Select: NM_003041
Type: single nucleotide variant
Location: chr16:31488679 (GRCh38)
Gene constraint: LOEUF 1.21 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.32 · 12 PDB
Residue 396: a disulfide bond; an α-helix

Full SLC5A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SLC5A2 p.Ala549Thr Uncertain significance ★★ ⚠ same condition
SLC5A2 p.Arg130His Uncertain significance ★★ ⚠ same condition
SLC5A2 p.Gly225Arg Uncertain significance ★★ ⚠ same condition
SLC5A2 p.Gly509Ser Uncertain significance ★★ ⚠ same condition
SLC5A2 p.Ser253Asn Uncertain significance ★★ ⚠ same condition
SLC5A2 p.Val346Met Uncertain significance ★★ ⚠ same condition
SLC5A2 p.Val385Ala Uncertain significance ★★ ⚠ same condition
SLC5A2 p.Val67Asp Uncertain significance ★★ ⚠ 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/slc5a2-p-ser396phe (accessed [today's date]).

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