Is CELA2A p.Arg228Trp (c.682C>T) pathogenic?

CELA2A p.Arg228Trp (c.682C>T) is classified Uncertain significance in CELA2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: ambiguous (0.3924); Very rare (popmax 0.00229%, nfe).

How common is CELA2A p.Arg228Trp (c.682C>T) in the general population?

CELA2A p.Arg228Trp (c.682C>T) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about CELA2A p.Arg228Trp (c.682C>T)?

AlphaMissense predicts ambiguous (score 0.3924) — an in-silico prediction, not a clinical call.

CELA2A p.Arg228Trp

c.682C>T · VCV4651832

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3924 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3924	ambiguous
REVEL	0.404	indeterminate
SaProt	LLR -13.04	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -4.3
Regional constraint	o/e 0.94	unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic
Overall
CADD	19.38	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 0.00229% European (non-Finnish) · 27/1,180,022 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00198% 29/1,461,658 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,254
European (non-Finnish)grpmax	0.00229%	43,705

Remaining individuals 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: CELA2A
Protein: p.Arg228Trp
Coding: c.682C>T
MANE Select: NM_033440
Type: single nucleotide variant
Location: chr1:15467428 (GRCh38)
Gene constraint: LOEUF 1.161 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.66
Residue 228: a disulfide bond; the peptidase s1 domain

Full CELA2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CELA2A p.Arg228Gln Likely benign ★ ⚠ same residue
CELA2A p.Leu85Met Likely pathogenic ★★ ⚠ same type
CELA2A p.Thr70Met Pathogenic ★★ same type
CELA2A p.Gln230Glu Likely benign ★★ same type
CELA2A p.Trp191Ter Likely pathogenic ★ same type
CELA2A c.356+5G>C Uncertain significance ★ same type
CELA2A p.Ala123Thr Uncertain significance ★ same type
CELA2A p.Ala145Val 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/cela2a-p-arg228trp (accessed [today's date]).

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