Is SPHK2 p.Pro407Ser (c.1219C>T) pathogenic?

SPHK2 p.Pro407Ser (c.1219C>T) is classified Uncertain significance in SPHK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-16). AlphaMissense: likely benign (0.0772); Very rare (popmax 0.000593%, nfe).

How common is SPHK2 p.Pro407Ser (c.1219C>T) in the general population?

SPHK2 p.Pro407Ser (c.1219C>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about SPHK2 p.Pro407Ser (c.1219C>T)?

AlphaMissense predicts likely benign (score 0.0772) — an in-silico prediction, not a clinical call.

SPHK2 p.Pro407Ser

c.1219C>T · rs2513890161 · VCV2245581

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0772 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0772	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 0.054, phastCons 0.7
Regional constraint	o/e 0.85	unconstrained · MANE · 8,680 bp · p 0.00015 · regional, not allelic
Overall
CADD	16.97	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 0.000593% European (non-Finnish) · 7/1,179,828 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,482 alleles · very rare exomes 7/1,461,218 · genomes 0/152,264 · joint denominator

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: SPHK2
Protein: p.Pro407Ser
Coding: c.1219C>T
MANE Select: NM_020126
dbSNP: rs2513890161
Type: single nucleotide variant
Location: chr19:48629027 (GRCh38)
Gene constraint: LOEUF 0.934 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.65
Residue 407: the 'disordered' region

Full SPHK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SPHK2 p.Ala506Ser Benign ★★ same type
SPHK2 p.Asp530Glu Likely benign ★★ same type
SPHK2 p.Ala141Ser Uncertain significance ★ ⚠ same type
SPHK2 p.Ala141Val Uncertain significance ★ ⚠ same type
SPHK2 p.Ala281Thr Uncertain significance ★ ⚠ same type
SPHK2 p.Ala295Val Uncertain significance ★ ⚠ same type
SPHK2 p.Ala367Thr Uncertain significance ★ ⚠ same type
SPHK2 p.Ala38Thr 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/sphk2-p-pro407ser (accessed [today's date]).

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