Is CELA3A p.Pro41Arg (c.122C>G) pathogenic?

CELA3A p.Pro41Arg (c.122C>G) is classified Uncertain significance in CELA3A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). AlphaMissense: ambiguous (0.4876); Very rare (popmax 6.33e-05%).

How common is CELA3A p.Pro41Arg (c.122C>G) in the general population?

CELA3A p.Pro41Arg (c.122C>G) is very rare (popmax 6.33e-05%) (gnomAD).

What do computational predictors say about CELA3A p.Pro41Arg (c.122C>G)?

AlphaMissense predicts ambiguous (score 0.4876) — an in-silico prediction, not a clinical call.

CELA3A p.Pro41Arg

c.122C>G · VCV4000102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4876 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.33e-05%)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4876	ambiguous
REVEL	0.874	moderately pathogenic-leaning
SaProt	LLR -11.79	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 11 kb · p 0.55 · regional, not allelic
Overall
CADD	24.9	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 6.33e-05%

Overall 6.33e-05% 1/1,578,572 alleles · very rare exomes 1/1,435,294 · genomes 0/143,278 · joint denominator

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: CELA3A
Protein: p.Pro41Arg
Coding: c.122C>G
MANE Select: NM_005747
Type: single nucleotide variant
Location: chr1:22003081 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.09
Residue 41: the peptidase s1 domain

Full CELA3A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CELA3A p.Pro41Ser Uncertain significance ★ ⚠ same residue
CELA3A p.Ala125Thr Uncertain significance ★ ⚠ same type
CELA3A p.Ala147Gly Uncertain significance ★ ⚠ same type
CELA3A p.Ala147Thr Uncertain significance ★ ⚠ same type
CELA3A p.Ala64Thr Uncertain significance ★ ⚠ same type
CELA3A p.Ala64Val Uncertain significance ★ ⚠ same type
CELA3A p.Arg115His Uncertain significance ★ ⚠ same type
CELA3A p.Arg179Gln 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/cela3a-p-pro41arg (accessed [today's date]).

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