Is C1QL4 p.Pro89Ala (c.265C>G) pathogenic?

C1QL4 p.Pro89Ala (c.265C>G) is classified Uncertain significance in C1QL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-28). AlphaMissense: likely benign (0.0744); Very rare (popmax 8.78e-05%, nfe).

How common is C1QL4 p.Pro89Ala (c.265C>G) in the general population?

C1QL4 p.Pro89Ala (c.265C>G) is very rare (popmax 8.78e-05%, nfe) (gnomAD).

What do computational predictors say about C1QL4 p.Pro89Ala (c.265C>G)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

C1QL4 p.Pro89Ala

c.265C>G · rs757095790 · VCV2267553

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.78e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.431	indeterminate
SaProt	LLR -8.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.78, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 3,420 bp · p 0.78 · regional, not allelic
Overall
CADD	18.48	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 8.78e-05% European (non-Finnish) · 1/1,138,798 alleles

Overall 6.56e-05% 1/1,525,422 alleles · very rare exomes 1/1,373,176 · genomes 0/152,246 · 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: C1QL4
Protein: p.Pro89Ala
Coding: c.265C>G
MANE Select: NM_001008223
dbSNP: rs757095790
Type: single nucleotide variant
Location: chr12:49336213 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.27 (gnomAD)
Structure: AlphaFold pLDDT 81.51
Residue 89: the collagen-like domain; the 'disordered' region

Full C1QL4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C1QL4 p.Ala114Gly Uncertain significance ★ ⚠ same type
C1QL4 p.Ala114Val Uncertain significance ★ ⚠ same type
C1QL4 p.Ala141Glu Uncertain significance ★ same type
C1QL4 p.Ala182Asp Uncertain significance ★ ⚠ same type
C1QL4 p.Arg109Cys Uncertain significance ★ ⚠ same type
C1QL4 p.Arg17His Uncertain significance ★ ⚠ same type
C1QL4 p.Arg38His Uncertain significance ★ ⚠ same type
C1QL4 p.Arg38Leu 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/c1ql4-p-pro89ala (accessed [today's date]).

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