Is CXADR p.Ser359Arg (c.1077C>G) pathogenic?

CXADR p.Ser359Arg (c.1077C>G) is classified Uncertain significance in CXADR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely pathogenic (0.9158); Very rare (popmax 0.00822%, nfe).

How common is CXADR p.Ser359Arg (c.1077C>G) in the general population?

CXADR p.Ser359Arg (c.1077C>G) is very rare (popmax 0.00822%, nfe) (gnomAD).

What do computational predictors say about CXADR p.Ser359Arg (c.1077C>G)?

AlphaMissense predicts likely pathogenic (score 0.9158) — an in-silico prediction, not a clinical call.

CXADR p.Ser359Arg

c.1077C>G · VCV4008505

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9158 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00822%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9158	likely pathogenic · top 10% in CXADR
REVEL	0.529	indeterminate
SaProt	LLR -6.65	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 6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 4,909 bp · p 0.0015 · regional, not allelic
Overall
CADD	25.3	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 0.00822% European (non-Finnish) · 97/1,179,830 alleles

Filtering AF 0.00689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.0062% 100/1,611,850 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00822%	12,163
Remaining individualsnot grpmax-eligible	0.00482%	20,767

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: CXADR
Protein: p.Ser359Arg
Coding: c.1077C>G
MANE Select: NM_001338
Type: single nucleotide variant
Location: chr21:17565671 (GRCh38)
Gene constraint: LOEUF 0.751 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.51 · 23 PDB

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

Similar variants

CXADR p.Thr193= Benign ★★ same type
CXADR p.Ala144Val Uncertain significance ★ ⚠ same type
CXADR p.Arg217Lys Uncertain significance ★ ⚠ same type
CXADR p.Arg226Pro Uncertain significance ★ ⚠ same type
CXADR p.Arg264Cys Uncertain significance ★ ⚠ same type
CXADR p.Arg287Cys Uncertain significance ★ ⚠ same type
CXADR p.Arg328His Uncertain significance ★ ⚠ same type
CXADR p.Arg90Gln 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/cxadr-p-ser359arg (accessed [today's date]).

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