Is C1RL p.Asp477Glu (c.1431C>G) pathogenic?

C1RL p.Asp477Glu (c.1431C>G) is classified Uncertain significance in C1RL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-20). AlphaMissense: likely benign (0.1572); Very rare (popmax 0.000848%, nfe).

How common is C1RL p.Asp477Glu (c.1431C>G) in the general population?

C1RL p.Asp477Glu (c.1431C>G) is very rare (popmax 0.000848%, nfe) (gnomAD).

What do computational predictors say about C1RL p.Asp477Glu (c.1431C>G)?

AlphaMissense predicts likely benign (score 0.1572) — an in-silico prediction, not a clinical call.

C1RL p.Asp477Glu

c.1431C>G · rs559175952 · VCV3135817

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1572 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000848%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1572	likely benign
REVEL	0.233	benign-leaning
SaProt	LLR -8.04	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 2.9	GERP 0.75, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 13 kb · p 0.015 · regional, not allelic
Overall
CADD	21.7	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 0.000848% European (non-Finnish) · 10/1,179,418 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.00062% 10/1,612,890 alleles · very rare

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: C1RL
Protein: p.Asp477Glu
Coding: c.1431C>G
MANE Select: NM_016546
dbSNP: rs559175952
Type: single nucleotide variant
Location: chr12:7096424 (GRCh38)
Gene constraint: LOEUF 1.205 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.42
Residue 477: the peptidase s1 domain

Full C1RL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C1RL p.Ala183Val Uncertain significance ★ ⚠ same type
C1RL p.Ala202Thr Uncertain significance ★ ⚠ same type
C1RL p.Ala271Asp Uncertain significance ★ ⚠ same type
C1RL p.Ala404Thr Uncertain significance ★ ⚠ same type
C1RL p.Ala45Thr Uncertain significance ★ ⚠ same type
C1RL p.Ala73Pro Uncertain significance ★ ⚠ same type
C1RL p.Ala95Pro Uncertain significance ★ ⚠ same type
C1RL p.Arg136Trp 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/c1rl-p-asp477glu (accessed [today's date]).

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