Is C1QL2 p.His252Pro (c.755A>C) pathogenic?

C1QL2 p.His252Pro (c.755A>C) is classified Uncertain significance in C1QL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-15). AlphaMissense: likely pathogenic (0.8183); Ultra-rare (popmax 0.0242%, sas).

How common is C1QL2 p.His252Pro (c.755A>C) in the general population?

C1QL2 p.His252Pro (c.755A>C) is ultra-rare (popmax 0.0242%, sas) (gnomAD).

What do computational predictors say about C1QL2 p.His252Pro (c.755A>C)?

AlphaMissense predicts likely pathogenic (score 0.8183) — an in-silico prediction, not a clinical call.

C1QL2 p.His252Pro

c.755A>C · rs527688201 · VCV2618535

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8183 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0242%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8183	likely pathogenic
REVEL	0.702	pathogenic-leaning
SaProt	LLR -11.46	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.1, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 170 bp · p 0.00023 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0242% South Asian · 22/91,080 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00142% 23/1,614,062 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0242%	4,140
Remaining individualsnot grpmax-eligible	0.0016%	62,502

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: C1QL2
Protein: p.His252Pro
Coding: c.755A>C
MANE Select: NM_182528
dbSNP: rs527688201
Type: single nucleotide variant
Location: chr2:119156911 (GRCh38)
Gene constraint: LOEUF 1.421 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.90
Residue 252: the c1q domain

Full C1QL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C1QL2 p.Ile32= Benign ★★ same type
C1QL2 p.Ala123Val Uncertain significance ★ ⚠ same type
C1QL2 p.Ala126Thr Uncertain significance ★ ⚠ same type
C1QL2 p.Ala16Thr Uncertain significance ★ ⚠ same type
C1QL2 p.Ala8Val Uncertain significance ★ ⚠ same type
C1QL2 p.Arg90Gln Uncertain significance ★ ⚠ same type
C1QL2 p.Arg90Gly Uncertain significance ★ ⚠ same type
C1QL2 p.Asp34Tyr 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/c1ql2-p-his252pro (accessed [today's date]).

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