Is C1QL4 p.Pro97Ser (c.289C>T) pathogenic?

C1QL4 p.Pro97Ser (c.289C>T) is classified Uncertain significance in C1QL4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-21). AlphaMissense: likely benign (0.0917); Ultra-rare (popmax 0.0102%, sas).

How common is C1QL4 p.Pro97Ser (c.289C>T) in the general population?

C1QL4 p.Pro97Ser (c.289C>T) is ultra-rare (popmax 0.0102%, sas) (gnomAD).

What do computational predictors say about C1QL4 p.Pro97Ser (c.289C>T)?

AlphaMissense predicts likely benign (score 0.0917) — an in-silico prediction, not a clinical call.

C1QL4 p.Pro97Ser

c.289C>T · rs773476928 · VCV2352954

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0917 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0917	likely benign
REVEL	0.381	indeterminate
SaProt	LLR -6.96	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP -0.69, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 3,420 bp · p 0.78 · regional, not allelic
Overall
CADD	19.44	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 0.0102% South Asian · 9/88,544 alleles

Filtering AF 0.00527% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00395%

Overall 0.0118% 187/1,583,348 alleles · ultra-rare exomes 174/1,431,206 · genomes 13/152,142 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.391%	256
Remaining individualsnot grpmax-eligible	0.0476%	2,101
South Asiangrpmax	0.0102%	9,838
European (non-Finnish)	0.00292%	34,279
Admixed American	0.00176%	56,860
African / African-American	0.00135%	74,214

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro97Ser
Coding: c.289C>T
MANE Select: NM_001008223
dbSNP: rs773476928
Type: single nucleotide variant
Location: chr12:49336189 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.27 (gnomAD)
Structure: AlphaFold pLDDT 81.51
Residue 97: 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-pro97ser (accessed [today's date]).

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