Is C1QL1 p.Pro59Ser (c.175C>T) pathogenic?

C1QL1 p.Pro59Ser (c.175C>T) is classified Uncertain significance in C1QL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-03). AlphaMissense: likely benign (0.0685); Very rare (popmax 0.00623%, afr).

How common is C1QL1 p.Pro59Ser (c.175C>T) in the general population?

C1QL1 p.Pro59Ser (c.175C>T) is very rare (popmax 0.00623%, afr) (gnomAD).

What do computational predictors say about C1QL1 p.Pro59Ser (c.175C>T)?

AlphaMissense predicts likely benign (score 0.0685) — an in-silico prediction, not a clinical call.

C1QL1 p.Pro59Ser

c.175C>T · VCV4217073

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0685 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00623%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0685	likely benign
REVEL	0.232	benign-leaning
SaProt	LLR -6.15	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP -0.75, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 7,857 bp · p 0.079 · regional, not allelic
Overall
CADD	20.3	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 0.00623% African / African-American · 4/64,250 alleles

Filtering AF 0.00205% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00128%

Overall 0.00145% 19/1,311,048 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00623%	16,063
Remaining individualsnot grpmax-eligible	0.00202%	49,402
European (non-Finnish)	0.00135%	74,293

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: C1QL1
Protein: p.Pro59Ser
Coding: c.175C>T
MANE Select: NM_006688
Type: single nucleotide variant
Location: chr17:44967874 (GRCh38)
Gene constraint: LOEUF 1.723 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.26
Residue 59: the 'disordered' region

Full C1QL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C1QL1 p.Pro59Arg Uncertain significance ★ ⚠ same residue
C1QL1 p.Ala113Val Uncertain significance ★ ⚠ same type
C1QL1 p.Ala131Thr Uncertain significance ★ ⚠ same type
C1QL1 p.Ala204Ser Uncertain significance ★ ⚠ same type
C1QL1 p.Ala226Pro Uncertain significance ★ ⚠ same type
C1QL1 p.Ala42Thr Uncertain significance ★ ⚠ same type
C1QL1 p.Arg29Leu Uncertain significance ★ ⚠ same type
C1QL1 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/c1ql1-p-pro59ser (accessed [today's date]).

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