Is CALY p.Arg176Cys (c.526C>T) pathogenic?

CALY p.Arg176Cys (c.526C>T) is classified Uncertain significance in CALY (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely benign (0.1507); Absent from gnomAD v4.1.

How common is CALY p.Arg176Cys (c.526C>T) in the general population?

CALY p.Arg176Cys (c.526C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CALY p.Arg176Cys (c.526C>T)?

AlphaMissense predicts likely benign (score 0.1507) — an in-silico prediction, not a clinical call.

CALY p.Arg176Cys

c.526C>T · VCV4218388

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1507 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,495,986)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1507	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -9.28	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 6.1	GERP 1.2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 3,159 bp · p 0.049 · regional, not allelic
Overall
CADD	22.3	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

No allele count reported in gnomAD v4.1 (AN 1,495,986). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CALY
Protein: p.Arg176Cys
Coding: c.526C>T
MANE Select: NM_015722
Type: single nucleotide variant
Location: chr10:133325955 (GRCh38)
Gene constraint: LOEUF 1.549 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.90
Residue 176: 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.Arg205Trp 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-arg176cys (accessed [today's date]).

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