Is CPLX4 p.Ala35Val (c.104C>T) pathogenic?

CPLX4 p.Ala35Val (c.104C>T) is classified Uncertain significance in CPLX4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-14). AlphaMissense: ambiguous (0.4285); Very rare (popmax 0.00223%, eas).

How common is CPLX4 p.Ala35Val (c.104C>T) in the general population?

CPLX4 p.Ala35Val (c.104C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CPLX4 p.Ala35Val (c.104C>T)?

AlphaMissense predicts ambiguous (score 0.4285) — an in-silico prediction, not a clinical call.

CPLX4 p.Ala35Val

c.104C>T · VCV3496417

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4285 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4285	ambiguous
REVEL	0.214	benign-leaning
SaProt	LLR -7.82	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 22 kb · p 0.99 · regional, not allelic
Overall
CADD	26.5	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 0.00223% East Asian · 1/44,868 alleles

Overall 6.84e-05% 1/1,461,666 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: CPLX4
Protein: p.Ala35Val
Coding: c.104C>T
MANE Select: NM_181654
Type: single nucleotide variant
Location: chr18:59318359 (GRCh38)
Gene constraint: LOEUF 1.729 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.26
Residue 35: the 'disordered' region

Full CPLX4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPLX4 p.Ala153Thr Uncertain significance ★ ⚠ same type
CPLX4 p.Ala36Gly Uncertain significance ★ ⚠ same type
CPLX4 p.Ala62Ser Uncertain significance ★ ⚠ same type
CPLX4 p.Arg107Trp Uncertain significance ★ ⚠ same type
CPLX4 p.Asp119Asn Uncertain significance ★ ⚠ same type
CPLX4 p.Asp60Glu Uncertain significance ★ ⚠ same type
CPLX4 p.Gln12Lys Uncertain significance ★ ⚠ same type
CPLX4 p.His76Leu 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/cplx4-p-ala35val (accessed [today's date]).

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