Is CACHD1 p.Val452Ile (c.1354G>A) pathogenic?

CACHD1 p.Val452Ile (c.1354G>A) is classified Uncertain significance in CACHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-30). AlphaMissense: likely benign (0.0784); Ultra-rare (popmax 0.0692%, eas); Associated with Inborn genetic diseases.

What condition is associated with CACHD1 p.Val452Ile (c.1354G>A)?

CACHD1 p.Val452Ile (c.1354G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CACHD1 p.Val452Ile (c.1354G>A) in the general population?

CACHD1 p.Val452Ile (c.1354G>A) is ultra-rare (popmax 0.0692%, eas) (gnomAD).

What do computational predictors say about CACHD1 p.Val452Ile (c.1354G>A)?

AlphaMissense predicts likely benign (score 0.0784) — an in-silico prediction, not a clinical call.

CACHD1 p.Val452Ile

c.1354G>A · rs201086698 · VCV2241317

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0784 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0692%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0784	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -6.02	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 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 203 kb · p 0.00059 · regional, not allelic
Overall
CADD	22.1	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 0.0692% East Asian · 31/44,828 alleles

Filtering AF 0.05% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0435%

Overall 0.00397% 64/1,613,710 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0692%	1,446
Remaining individualsnot grpmax-eligible	0.024%	4,166
Admixed American	0.005%	19,987
South Asian	0.0022%	45,477
African / African-American	0.00133%	75,034
European (non-Finnish)	0.00102%	98,324

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: CACHD1
Protein: p.Val452Ile
Coding: c.1354G>A
MANE Select: NM_020925
dbSNP: rs201086698
Type: single nucleotide variant
Location: chr1:64647998 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.76

Full CACHD1 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

CACHD1 p.Ala1058Val Uncertain significance ★ ⚠ same condition
CACHD1 p.Ala1113Val Uncertain significance ★ ⚠ same condition
CACHD1 p.Ala116Thr Uncertain significance ★ ⚠ same condition
CACHD1 p.Ala1170Thr Uncertain significance ★ ⚠ same condition
CACHD1 p.Ala1263Val Uncertain significance ★ ⚠ same condition
CACHD1 p.Ala257Thr Uncertain significance ★ ⚠ same condition
CACHD1 p.Ala314Thr Uncertain significance ★ ⚠ same condition
CACHD1 p.Ala314Val 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/cachd1-p-val452ile (accessed [today's date]).

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