Is CPQ p.Trp412Ser (c.1235G>C) pathogenic?

CPQ p.Trp412Ser (c.1235G>C) is classified Uncertain significance in CPQ (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-19). AlphaMissense: likely pathogenic (0.8635); Very rare (popmax 0.000424%, nfe).

How common is CPQ p.Trp412Ser (c.1235G>C) in the general population?

CPQ p.Trp412Ser (c.1235G>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about CPQ p.Trp412Ser (c.1235G>C)?

AlphaMissense predicts likely pathogenic (score 0.8635) — an in-silico prediction, not a clinical call.

CPQ p.Trp412Ser

c.1235G>C · rs750399271 · VCV2272285

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8635 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8635	likely pathogenic · top 10% in CPQ
REVEL	0.626	indeterminate
SaProt	LLR -9.81	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 358 kb · p 0.13 · regional, not allelic
Overall
CADD	28.9	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 0.000424% European (non-Finnish) · 5/1,178,794 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000343% 5/1,457,482 alleles · very rare

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: CPQ
Protein: p.Trp412Ser
Coding: c.1235G>C
MANE Select: NM_016134
dbSNP: rs750399271
Type: single nucleotide variant
Location: chr8:97066190 (GRCh38)
Gene constraint: LOEUF 1.077 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.81

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

Similar variants

CPQ p.Ile139Thr Uncertain significance ★★ ⚠ same type
CPQ p.Ile204Val Benign ★★ ⚠ same type
CPQ p.Leu151Pro Benign ★★ same type
CPQ p.Leu330= Benign ★★ same type
CPQ p.Ser138Asn Benign ★★ same type
CPQ p.Tyr92Asp Benign ★★ ⚠ same type
CPQ p.Ala131Thr Uncertain significance ★ ⚠ same type
CPQ p.Ala191Val 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/cpq-p-trp412ser (accessed [today's date]).

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