Is CELA2A p.Arg240Cys (c.718C>T) pathogenic?

CELA2A p.Arg240Cys (c.718C>T) is classified Uncertain significance in CELA2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely pathogenic (0.7095); Ultra-rare (popmax 0.0167%, amr).

How common is CELA2A p.Arg240Cys (c.718C>T) in the general population?

CELA2A p.Arg240Cys (c.718C>T) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about CELA2A p.Arg240Cys (c.718C>T)?

AlphaMissense predicts likely pathogenic (score 0.7095) — an in-silico prediction, not a clinical call.

CELA2A p.Arg240Cys

c.718C>T · VCV4000085

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7095 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7095	likely pathogenic
REVEL	0.484	indeterminate
SaProt	LLR -9.40	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -4.3
Regional constraint	o/e 0.94	unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic
Overall
CADD	10.68	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 0.0167% Admixed American · 10/60,004 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00304% 49/1,614,048 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	6,000
Remaining individualsnot grpmax-eligible	0.008%	12,498
European (non-Finnish)	0.00263%	38,066
South Asian	0.0022%	45,546
African / African-American	0.00133%	74,932

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.Arg240Cys
Coding: c.718C>T
MANE Select: NM_033440
Type: single nucleotide variant
Location: chr1:15467464 (GRCh38)
Gene constraint: LOEUF 1.161 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.66
Residue 240: 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.Arg240His Uncertain significance ★ ⚠ 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-arg240cys (accessed [today's date]).

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