Is CACHD1 p.Pro665Arg (c.1994C>G) pathogenic?

CACHD1 p.Pro665Arg (c.1994C>G) is classified Uncertain significance in CACHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-23). AlphaMissense: likely pathogenic (0.9959); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with CACHD1 p.Pro665Arg (c.1994C>G)?

CACHD1 p.Pro665Arg (c.1994C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CACHD1 p.Pro665Arg (c.1994C>G) in the general population?

CACHD1 p.Pro665Arg (c.1994C>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CACHD1 p.Pro665Arg (c.1994C>G)?

AlphaMissense predicts likely pathogenic (score 0.9959) — an in-silico prediction, not a clinical call.

CACHD1 p.Pro665Arg

c.1994C>G · VCV3826566

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9959 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9959	likely pathogenic · top 8% in CACHD1
REVEL	0.345	indeterminate
SaProt	LLR -11.04	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 203 kb · p 0.00059 · regional, not allelic
Overall
CADD	28.3	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00217% 35/1,613,942 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Finnishnot grpmax-eligible	0.0156%	6,402
Admixed American	0.00333%	29,986
African / African-American	0.00267%	37,442
European (non-Finnish)	0.00169%	59,001

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.Pro665Arg
Coding: c.1994C>G
MANE Select: NM_020925
Type: single nucleotide variant
Location: chr1:64663737 (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

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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-pro665arg (accessed [today's date]).

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