Is SPHK2 p.Pro83= (c.249T>G) pathogenic?

SPHK2 p.Pro83= (c.249T>G) is classified Likely benign in SPHK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-01). Rare (popmax 0.442%, nfe).

How common is SPHK2 p.Pro83= (c.249T>G) in the general population?

SPHK2 p.Pro83= (c.249T>G) is rare (popmax 0.442%, nfe) (gnomAD).

SPHK2 p.Pro83=

c.249T>G · rs151257086 · VCV2650213

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.442%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.3	GERP -3.3
Overall
CADD	0.546	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.442% European (non-Finnish) · 5,208/1,178,794 alleles

Filtering AF 0.432% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.428%

Overall 0.422% 6,805/1,611,390 alleles · rare exomes 6,142/1,459,042 · genomes 663/152,348 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.04%	49
European (non-Finnish)grpmax	0.442%	226
Remaining individualsnot grpmax-eligible	0.292%	343
Middle Eastern	0.149%	673
Admixed American	0.0935%	1,069
Ashkenazi Jewishnot grpmax-eligible	0.0677%	1,477
African / African-American	0.0293%	3,410
South Asian	0.0231%	4,332
East Asian	0.00223%	44,816

Finnish 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: SPHK2
Protein: p.Pro83=
Coding: c.249T>G
MANE Select: NM_020126
dbSNP: rs151257086
Type: single nucleotide variant
Location: chr19:48626100 (GRCh38)
Gene constraint: LOEUF 0.934 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.65
Residue 83: the 'required for binding to sulfatide and phosphoinositides and for membrane localizatione' 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-pro83 (accessed [today's date]).

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