Is CANX p.Ser81Ala (c.241T>G) pathogenic?

CANX p.Ser81Ala (c.241T>G) is classified Uncertain significance in CANX (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-28). AlphaMissense: likely benign (0.068); Ultra-rare (popmax 0.0714%, amr).

How common is CANX p.Ser81Ala (c.241T>G) in the general population?

CANX p.Ser81Ala (c.241T>G) is ultra-rare (popmax 0.0714%, amr) (gnomAD).

What do computational predictors say about CANX p.Ser81Ala (c.241T>G)?

AlphaMissense predicts likely benign (score 0.068) — an in-silico prediction, not a clinical call.

CANX p.Ser81Ala

c.241T>G · rs766551548 · VCV2362067

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.068 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0714%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.068	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -5.90	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 3.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 15 kb · p 7e-05 · regional, not allelic
Overall
CADD	18.96	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 0.0714% Admixed American · 42/58,862 alleles

Filtering AF 0.0542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0482%

Overall 0.00403% 63/1,562,582 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0714%	1,401
Middle Eastern	0.0167%	5,996
South Asian	0.00338%	29,629
Remaining individualsnot grpmax-eligible	0.00329%	30,353
European (non-Finnish)	0.00132%	75,711

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.Ser81Ala
Coding: c.241T>G
MANE Select: NM_001746
dbSNP: rs766551548
Type: single nucleotide variant
Location: chr5:179706327 (GRCh38)
Gene constraint: LOEUF 0.268 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.15

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-ser81ala (accessed [today's date]).

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