Is SPCS2 p.Phe93Ser (c.278T>C) pathogenic?

SPCS2 p.Phe93Ser (c.278T>C) is classified Uncertain significance in SPCS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). AlphaMissense: ambiguous (0.4403); Very rare (popmax 0.00167%, amr).

How common is SPCS2 p.Phe93Ser (c.278T>C) in the general population?

SPCS2 p.Phe93Ser (c.278T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about SPCS2 p.Phe93Ser (c.278T>C)?

AlphaMissense predicts ambiguous (score 0.4403) — an in-silico prediction, not a clinical call.

SPCS2 p.Phe93Ser

c.278T>C · VCV3448220

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4403 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4403	ambiguous
REVEL	0.19	benign-leaning
SaProt	LLR -8.98	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 6.1, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 28 kb · p 1e-15 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,996 alleles

Overall 0.000124% 2/1,613,436 alleles · very rare exomes 1/1,461,122 · genomes 1/152,314 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,996
African / African-American	0.00133%	75,030

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.Phe93Ser
Coding: c.278T>C
MANE Select: NM_014752
Type: single nucleotide variant
Location: chr11:74965842 (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-phe93ser (accessed [today's date]).

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