Is CAPSL p.Met75Ile (c.225G>A) pathogenic?

CAPSL p.Met75Ile (c.225G>A) is classified Uncertain significance in CAPSL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-16). AlphaMissense: ambiguous (0.3756); Very rare (popmax 0.000593%, nfe).

How common is CAPSL p.Met75Ile (c.225G>A) in the general population?

CAPSL p.Met75Ile (c.225G>A) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about CAPSL p.Met75Ile (c.225G>A)?

AlphaMissense predicts ambiguous (score 0.3756) — an in-silico prediction, not a clinical call.

CAPSL p.Met75Ile

c.225G>A · rs1424175093 · VCV2307494

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3756 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3756	ambiguous
REVEL	0.152	moderately benign-leaning
SaProt	LLR -9.22	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.33	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 1.8	GERP 1.6, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 17 kb · p 0.065 · regional, not allelic
Overall
CADD	18.62	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,179,580 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000479% 7/1,461,320 alleles · very rare

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: CAPSL
Protein: p.Met75Ile
Coding: c.225G>A
MANE Select: NM_001042625
dbSNP: rs1424175093
Type: single nucleotide variant
Location: chr5:35910456 (GRCh38)
Gene constraint: LOEUF 1.17 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.88 · 1 PDB
Residue 75: the ef-hand 2 domain

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

Similar variants

CAPSL p.Phe61Val Uncertain significance ★★ ⚠ same type
CAPSL p.Met201Val Benign ★★ ⚠ same type
CAPSL p.Ala2Ser Uncertain significance ★ ⚠ same type
CAPSL p.Arg137Cys Uncertain significance ★ ⚠ same type
CAPSL p.Arg137His Uncertain significance ★ ⚠ same type
CAPSL p.Arg137Leu Uncertain significance ★ ⚠ same type
CAPSL p.Arg160Thr Uncertain significance ★ ⚠ same type
CAPSL p.Asp135Glu 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/capsl-p-met75ile (accessed [today's date]).

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