Is SPEG p.Pro322Ser (c.964C>T) pathogenic?

SPEG p.Pro322Ser (c.964C>T) is classified Uncertain significance in SPEG (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-10). AlphaMissense: likely benign (0.1486); Ultra-rare (popmax 0.0525%, amr); Associated with Inborn genetic diseases.

What condition is associated with SPEG p.Pro322Ser (c.964C>T)?

SPEG p.Pro322Ser (c.964C>T) is associated with Inborn genetic diseases (ClinVar).

How common is SPEG p.Pro322Ser (c.964C>T) in the general population?

SPEG p.Pro322Ser (c.964C>T) is ultra-rare (popmax 0.0525%, amr) (gnomAD).

What do computational predictors say about SPEG p.Pro322Ser (c.964C>T)?

AlphaMissense predicts likely benign (score 0.1486) — an in-silico prediction, not a clinical call.

SPEG p.Pro322Ser

c.964C>T · rs764502382 · VCV1445222

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1486 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0525%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1486	likely benign
REVEL	0.048	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 0.46	GERP -2.4, phastCons 0.012
Regional constraint	o/e 0.97	unconstrained · MANE · 27 kb · p 0.32 · regional, not allelic
Overall
CADD	12.4	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 0.0525% Admixed American · 31/59,068 alleles

Filtering AF 0.038% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.033%

Overall 0.0109% 175/1,603,554 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0525%	1,905
Finnishnot grpmax-eligible	0.0275%	3,634
Remaining individualsnot grpmax-eligible	0.0242%	4,128
Middle Eastern	0.0167%	5,988
African / African-American	0.00937%	10,667
European (non-Finnish)	0.00885%	11,300

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.Pro322Ser
Coding: c.964C>T
MANE Select: NM_005876
dbSNP: rs764502382
Type: single nucleotide variant
Location: chr2:219448122 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI <0.01 (gnomAD)
Residue 322: 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.Pro322Leu Uncertain significance ★ ⚠ 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
SPEG p.Ala241Thr 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-pro322ser (accessed [today's date]).

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