Is CALY p.Pro192Arg (c.575C>G) pathogenic?

CALY p.Pro192Arg (c.575C>G) is classified Uncertain significance in CALY (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-24). AlphaMissense: likely benign (0.0904); Rare (popmax 0.114%, sas).

How common is CALY p.Pro192Arg (c.575C>G) in the general population?

CALY p.Pro192Arg (c.575C>G) is rare (popmax 0.114%, sas) (gnomAD).

What do computational predictors say about CALY p.Pro192Arg (c.575C>G)?

AlphaMissense predicts likely benign (score 0.0904) — an in-silico prediction, not a clinical call.

CALY p.Pro192Arg

c.575C>G · rs987402732 · VCV2346192

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0904 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.114%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0904	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -6.80	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 8.2	GERP 0.12, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 3,159 bp · p 0.049 · regional, not allelic
Overall
CADD	21.7	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 0.114% South Asian · 45/39,564 alleles

Filtering AF 0.0873% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.078%

Overall 0.00355% 46/1,293,992 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.114%	879
Remaining individualsnot grpmax-eligible	0.00207%	48,286

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: CALY
Protein: p.Pro192Arg
Coding: c.575C>G
MANE Select: NM_015722
dbSNP: rs987402732
Type: single nucleotide variant
Location: chr10:133325906 (GRCh38)
Gene constraint: LOEUF 1.549 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.90
Residue 192: the 'disordered' region

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

Similar variants

CALY p.Ala150Asp Uncertain significance ★ ⚠ same type
CALY p.Ala187Glu Uncertain significance ★ ⚠ same type
CALY p.Ala23Pro Uncertain significance ★ ⚠ same type
CALY p.Ala86Ser Uncertain significance ★ ⚠ same type
CALY p.Ala86Thr Uncertain significance ★ ⚠ same type
CALY p.Ala94Val Uncertain significance ★ ⚠ same type
CALY p.Arg120Trp Uncertain significance ★ ⚠ same type
CALY p.Arg176Cys 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/caly-p-pro192arg (accessed [today's date]).

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