Is C1QL3 p.Pro125Ser (c.373C>T) pathogenic?

C1QL3 p.Pro125Ser (c.373C>T) is classified Uncertain significance in C1QL3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-05). AlphaMissense: likely pathogenic (0.7751); Very rare (popmax 0.00673%, amr).

How common is C1QL3 p.Pro125Ser (c.373C>T) in the general population?

C1QL3 p.Pro125Ser (c.373C>T) is very rare (popmax 0.00673%, amr) (gnomAD).

What do computational predictors say about C1QL3 p.Pro125Ser (c.373C>T)?

AlphaMissense predicts likely pathogenic (score 0.7751) — an in-silico prediction, not a clinical call.

C1QL3 p.Pro125Ser

c.373C>T · VCV3483380

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7751 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00673%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7751	likely pathogenic
REVEL	0.234	benign-leaning
SaProt	LLR -10.86	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 6,368 bp · p 0.003 · regional, not allelic
Overall
CADD	33.0	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 0.00673% Admixed American · 4/59,476 alleles

Filtering AF 0.00227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000825% 12/1,454,190 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00673%	14,869
European (non-Finnish)	0.00068%	147,059

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: C1QL3
Protein: p.Pro125Ser
Coding: c.373C>T
MANE Select: NM_001010908
Type: single nucleotide variant
Location: chr10:16520693 (GRCh38)
Gene constraint: LOEUF 0.788 · pLI 0.54 (gnomAD)
Structure: AlphaFold pLDDT 80.16
Residue 125: the c1q domain

Full C1QL3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C1QL3 p.Leu152= Benign ★★ same type
C1QL3 p.Ala40Val Uncertain significance ★ ⚠ same type
C1QL3 p.Arg98Pro Uncertain significance ★ ⚠ same type
C1QL3 p.Asn111Lys Uncertain significance ★ ⚠ same type
C1QL3 p.Asp48His Uncertain significance ★ ⚠ same type
C1QL3 p.Gln99Pro Uncertain significance ★ ⚠ same type
C1QL3 p.Glu23Lys Uncertain significance ★ ⚠ same type
C1QL3 p.Glu92Gln 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/c1ql3-p-pro125ser (accessed [today's date]).

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