Is CANX p.Asp335Gly (c.1004A>G) pathogenic?

CANX p.Asp335Gly (c.1004A>G) is classified Uncertain significance in CANX (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-04). AlphaMissense: likely benign (0.1473); Very rare (popmax 0.00402%, afr).

How common is CANX p.Asp335Gly (c.1004A>G) in the general population?

CANX p.Asp335Gly (c.1004A>G) is very rare (popmax 0.00402%, afr) (gnomAD).

What do computational predictors say about CANX p.Asp335Gly (c.1004A>G)?

AlphaMissense predicts likely benign (score 0.1473) — an in-silico prediction, not a clinical call.

CANX p.Asp335Gly

c.1004A>G · rs779436099 · VCV2543819

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1473 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00402%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1473	likely benign
REVEL	0.256	benign-leaning
SaProt	LLR -8.07	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 5.2	GERP 0.76, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 15 kb · p 7e-05 · regional, not allelic
Overall
CADD	23.1	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 0.00402% African / African-American · 3/74,614 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000811% 13/1,603,522 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00402%	24,871
European (non-Finnish)	0.000853%	117,233

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: CANX
Protein: p.Asp335Gly
Coding: c.1004A>G
MANE Select: NM_001746
dbSNP: rs779436099
Type: single nucleotide variant
Location: chr5:179719760 (GRCh38)
Gene constraint: LOEUF 0.268 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.15
Residue 335: the 'disordered' region; the 'p domain (extended arm)' region; the '4 x approximate repeats' region; the 'interaction with ppib' region

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

Similar variants

CANX p.Ala20Ser Uncertain significance ★ ⚠ same type
CANX p.Ala336Thr Uncertain significance ★ ⚠ same type
CANX p.Ala421Val Uncertain significance ★ ⚠ same type
CANX p.Ala460Thr Uncertain significance ★ ⚠ same type
CANX p.Arg415Ile Uncertain significance ★ ⚠ same type
CANX p.Arg480Leu Uncertain significance ★ ⚠ same type
CANX p.Arg590Gln Uncertain significance ★ ⚠ same type
CANX p.Asp142Gly 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/canx-p-asp335gly (accessed [today's date]).

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