Is CAPN1 p.Arg385Gln (c.1154G>A) pathogenic?

CAPN1 p.Arg385Gln (c.1154G>A) is classified Uncertain significance in CAPN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-04). AlphaMissense: likely pathogenic (0.9447); Very rare (popmax 0.00239%, eas); Associated with Inborn genetic diseases.

What condition is associated with CAPN1 p.Arg385Gln (c.1154G>A)?

CAPN1 p.Arg385Gln (c.1154G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CAPN1 p.Arg385Gln (c.1154G>A) in the general population?

CAPN1 p.Arg385Gln (c.1154G>A) is very rare (popmax 0.00239%, eas) (gnomAD).

What do computational predictors say about CAPN1 p.Arg385Gln (c.1154G>A)?

AlphaMissense predicts likely pathogenic (score 0.9447) — an in-silico prediction, not a clinical call.

CAPN1 p.Arg385Gln

c.1154G>A · VCV3484714

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9447 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00239%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9447	likely pathogenic
REVEL	0.726	pathogenic-leaning
SaProt	LLR -13.88	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 2.6, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 29 kb · p 4.3e-06 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00239% East Asian · 1/41,866 alleles

Filtering AF 0.000778% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000617%

Overall 0.00134% 21/1,570,248 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00659%	15,181
East Asiangrpmax	0.00239%	41,866
Remaining individualsnot grpmax-eligible	0.00164%	60,850
European (non-Finnish)	0.0013%	77,205

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CAPN1
Protein: p.Arg385Gln
Coding: c.1154G>A
MANE Select: NM_005186
Type: single nucleotide variant
Location: chr11:65188735 (GRCh38)
Gene constraint: LOEUF 0.977 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.03 · 5 PDB
Residue 385: the 'domain iii' region

Full CAPN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CAPN1 p.Arg385Ter Pathogenic/Likely pathogenic ★★ same residue
CAPN1 p.Arg104His Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg293Gln Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg293Trp Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg347Cys Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg347His Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg48Gln Uncertain significance ★★ ⚠ same condition
CAPN1 p.Arg581Gln Uncertain significance ★★ ⚠ same condition

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/capn1-p-arg385gln (accessed [today's date]).

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