Is SPCS2 p.Ser213Ala (c.637T>G) pathogenic?

SPCS2 p.Ser213Ala (c.637T>G) is classified Uncertain significance in SPCS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely benign (0.1642); Very rare (popmax 0.00409%, afr).

How common is SPCS2 p.Ser213Ala (c.637T>G) in the general population?

SPCS2 p.Ser213Ala (c.637T>G) is very rare (popmax 0.00409%, afr) (gnomAD).

What do computational predictors say about SPCS2 p.Ser213Ala (c.637T>G)?

AlphaMissense predicts likely benign (score 0.1642) — an in-silico prediction, not a clinical call.

SPCS2 p.Ser213Ala

c.637T>G · VCV4588725

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1642 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00409%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1642	likely benign
REVEL	0.134	moderately benign-leaning
SaProt	LLR -6.04	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 6.2	GERP 5.9, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 28 kb · p 1e-15 · regional, not allelic
Overall
CADD	23.2	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00409% African / African-American · 3/73,406 alleles

Filtering AF 0.00109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000501%

Overall 0.00019% 3/1,582,834 alleles · very rare exomes 1/1,431,786 · genomes 2/151,048 · joint denominator

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: SPCS2
Protein: p.Ser213Ala
Coding: c.637T>G
MANE Select: NM_014752
Type: single nucleotide variant
Location: chr11:74976999 (GRCh38)
Gene constraint: LOEUF 0.389 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 65.48 · 4 PDB

Full SPCS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SPCS2 p.Ala207Val Uncertain significance ★ ⚠ same type
SPCS2 p.Ala95Gly Uncertain significance ★ ⚠ same type
SPCS2 p.Arg185Gln Uncertain significance ★ ⚠ same type
SPCS2 p.Arg214Lys Uncertain significance ★ ⚠ same type
SPCS2 p.Asn77Ser Uncertain significance ★ ⚠ same type
SPCS2 p.Gln184Arg Uncertain significance ★ ⚠ same type
SPCS2 p.Glu188Gly Uncertain significance ★ same type
SPCS2 p.Gly16Val 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/spcs2-p-ser213ala (accessed [today's date]).

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