Is SPCS2 p.Lys65Arg (c.194A>G) pathogenic?

SPCS2 p.Lys65Arg (c.194A>G) is classified Uncertain significance in SPCS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-25). AlphaMissense: likely benign (0.228); Absent from gnomAD v4.1.

How common is SPCS2 p.Lys65Arg (c.194A>G) in the general population?

SPCS2 p.Lys65Arg (c.194A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SPCS2 p.Lys65Arg (c.194A>G)?

AlphaMissense predicts likely benign (score 0.228) — an in-silico prediction, not a clinical call.

SPCS2 p.Lys65Arg

c.194A>G · rs1948536125 · VCV2613567

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.228 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.228	likely benign
REVEL	0.217	benign-leaning
SaProt	LLR -6.92	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 11	GERP 6.1, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 28 kb · p 1e-15 · regional, not allelic
Overall
CADD	24.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SPCS2
Protein: p.Lys65Arg
Coding: c.194A>G
MANE Select: NM_014752
dbSNP: rs1948536125
Type: single nucleotide variant
Location: chr11:74965113 (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-lys65arg (accessed [today's date]).

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