Is SPEG p.Pro845Ser (c.2533C>T) pathogenic?

SPEG p.Pro845Ser (c.2533C>T) is classified Uncertain significance in SPEG (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-20). AlphaMissense: likely benign (0.1333); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with SPEG p.Pro845Ser (c.2533C>T)?

SPEG p.Pro845Ser (c.2533C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SPEG p.Pro845Ser (c.2533C>T) in the general population?

SPEG p.Pro845Ser (c.2533C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about SPEG p.Pro845Ser (c.2533C>T)?

AlphaMissense predicts likely benign (score 0.1333) — an in-silico prediction, not a clinical call.

SPEG p.Pro845Ser

c.2533C>T · rs369395171 · VCV1460916

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1333 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1333	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.28, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.32 · regional, not allelic
Overall
CADD	15.87	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 0.0011% South Asian · 1/91,062 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000744% 12/1,613,556 alleles · very rare exomes 11/1,461,496 · genomes 1/152,060 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,584
Remaining individualsnot grpmax-eligible	0.0032%	31,233
South Asiangrpmax	0.0011%	91,062
European (non-Finnish)	0.000678%	147,485

Ashkenazi Jewish 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: SPEG
Protein: p.Pro845Ser
Coding: c.2533C>T
MANE Select: NM_005876
dbSNP: rs369395171
Type: single nucleotide variant
Location: chr2:219461974 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI <0.01 (gnomAD)
Residue 845: the 'disordered' region

Full SPEG 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

SPEG p.Pro845Ala Uncertain significance ★ ⚠ same residue
SPEG p.Pro845= Likely benign ★ same residue
SPEG p.Ala1249Thr Uncertain significance ★★ ⚠ same condition
SPEG p.Ala1334Val Uncertain significance ★★ ⚠ same condition
SPEG p.Ala1628Val Uncertain significance ★★ same condition
SPEG p.Ala1686Thr Uncertain significance ★★ ⚠ same condition
SPEG p.Ala199Val Uncertain significance ★★ ⚠ same condition
SPEG p.Ala220Ser 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/speg-p-pro845ser (accessed [today's date]).

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