Is C1QA p.Leu166Pro (c.497T>C) pathogenic?

C1QA p.Leu166Pro (c.497T>C) is classified Uncertain significance in C1QA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-08). AlphaMissense: likely pathogenic (0.5794); Ultra-rare (popmax 0.0208%, nfe).

How common is C1QA p.Leu166Pro (c.497T>C) in the general population?

C1QA p.Leu166Pro (c.497T>C) is ultra-rare (popmax 0.0208%, nfe) (gnomAD).

What do computational predictors say about C1QA p.Leu166Pro (c.497T>C)?

AlphaMissense predicts likely pathogenic (score 0.5794) — an in-silico prediction, not a clinical call.

C1QA p.Leu166Pro

c.497T>C · rs200812579 · VCV1489296

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5794 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0208%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.5794	likely pathogenic
REVEL	0.315	indeterminate
SaProt	LLR -7.41	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 2.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 1,787 bp · p 0.003 · regional, not allelic
Overall
CADD	22.7	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 0.0208% European (non-Finnish) · 246/1,180,042 alleles

Filtering AF 0.0187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0179%

Overall 0.0157% 253/1,614,112 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0208%	4,797
Remaining individualsnot grpmax-eligible	0.0096%	10,415
Admixed American	0.00167%	60,012

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: C1QA
Protein: p.Leu166Pro
Coding: c.497T>C
MANE Select: NM_015991
dbSNP: rs200812579
Type: single nucleotide variant
Location: chr1:22639166 (GRCh38)
Gene constraint: LOEUF 0.997 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 83.68 · 11 PDB
Residue 166: the c1q domain; a β-strand

Full C1QA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C1QA p.Leu166= Likely benign ★ same residue
C1QA p.Arg27Ter Pathogenic/Likely pathogenic ★★ same type
C1QA p.Gln208Ter Pathogenic ★★ same type
C1QA p.Gly157Asp Likely pathogenic ★★ same type
C1QA p.Arg150Gln Uncertain significance ★★ ⚠ same type
C1QA p.Arg180Lys Uncertain significance ★★ ⚠ same type
C1QA p.Arg27Gln Uncertain significance ★★ ⚠ same type
C1QA p.Arg42Gln 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/c1qa-p-leu166pro (accessed [today's date]).

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