Is SPHK2 p.Pro504Ser (c.1510C>T) pathogenic?

SPHK2 p.Pro504Ser (c.1510C>T) is classified Likely benign in SPHK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-09). AlphaMissense: likely benign (0.0665); Rare (popmax 0.263%, amr).

How common is SPHK2 p.Pro504Ser (c.1510C>T) in the general population?

SPHK2 p.Pro504Ser (c.1510C>T) is rare (popmax 0.263%, amr) (gnomAD).

What do computational predictors say about SPHK2 p.Pro504Ser (c.1510C>T)?

AlphaMissense predicts likely benign (score 0.0665) — an in-silico prediction, not a clinical call.

SPHK2 p.Pro504Ser

c.1510C>T · rs139877170 · VCV778172

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0665 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.263%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0665	likely benign
REVEL	0.01	strongly benign-leaning
SaProt	LLR -7.14	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 -0.49	GERP -3.3
Regional constraint	o/e 1.14	unconstrained · MANE · 574 bp · p 0.023 · regional, not allelic
Overall
CADD	0.445	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 0.263% Admixed American · 158/60,032 alleles

Filtering AF 0.23% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.217%

Overall 0.0984% 1,588/1,613,326 alleles · rare exomes 1,461/1,460,964 · genomes 127/152,362 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.263%	380
Middle Eastern	0.115%	866
Remaining individualsnot grpmax-eligible	0.11%	906
European (non-Finnish)	0.11%	908
Finnishnot grpmax-eligible	0.0395%	2,530
African / African-American	0.0253%	3,951
Ashkenazi Jewishnot grpmax-eligible	0.0169%	5,918
East Asian	0.0111%	8,976

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.Pro504Ser
Coding: c.1510C>T
MANE Select: NM_020126
dbSNP: rs139877170
Type: single nucleotide variant
Location: chr19:48629318 (GRCh38)
Gene constraint: LOEUF 0.934 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.65
Residue 504: 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-pro504ser (accessed [today's date]).

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