Is SPEG p.Pro533Ser (c.1597C>T) pathogenic?

SPEG p.Pro533Ser (c.1597C>T) is classified Uncertain significance in SPEG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-13). AlphaMissense: likely benign (0.1436); Very rare (popmax 0.00657%, sas).

How common is SPEG p.Pro533Ser (c.1597C>T) in the general population?

SPEG p.Pro533Ser (c.1597C>T) is very rare (popmax 0.00657%, sas) (gnomAD).

What do computational predictors say about SPEG p.Pro533Ser (c.1597C>T)?

AlphaMissense predicts likely benign (score 0.1436) — an in-silico prediction, not a clinical call.

SPEG p.Pro533Ser

c.1597C>T · rs779175668 · VCV1478985

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1436 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00657%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1436	likely benign
REVEL	0.096	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.5	GERP 1.3, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.32 · regional, not allelic
Overall
CADD	23.0	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00657% South Asian · 5/76,144 alleles

Filtering AF 0.00252% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00194%

Overall 0.00273% 40/1,466,124 alleles · very rare exomes 38/1,314,002 · genomes 2/152,122 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00657%	15,229
European (non-Finnish)	0.00305%	32,810
East Asian	0.00291%	34,374

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: SPEG
Protein: p.Pro533Ser
Coding: c.1597C>T
MANE Select: NM_005876
dbSNP: rs779175668
Type: single nucleotide variant
Location: chr2:219448755 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI <0.01 (gnomAD)
Residue 533: the 'disordered' region

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

Similar variants

SPEG p.Arg1467Ter Likely pathogenic ★★ same type
SPEG p.Ser131Ter Pathogenic/Likely pathogenic ★★ same type
SPEG c.3301+5G>A Uncertain significance ★★ same type
SPEG c.478+5G>A Uncertain significance ★★ same type
SPEG p.Ala121Thr Uncertain significance ★★ same type
SPEG p.Ala1249Thr Uncertain significance ★★ ⚠ same type
SPEG p.Ala1334Val Uncertain significance ★★ ⚠ same type
SPEG p.Ala154Asp 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/speg-p-pro533ser (accessed [today's date]).

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