Is CACHD1 p.Pro1234Ser (c.3700C>T) pathogenic?

CACHD1 p.Pro1234Ser (c.3700C>T) is classified Uncertain significance in CACHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-11). AlphaMissense: ambiguous (0.4777); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CACHD1 p.Pro1234Ser (c.3700C>T)?

CACHD1 p.Pro1234Ser (c.3700C>T) is associated with Inborn genetic diseases (ClinVar).

How common is CACHD1 p.Pro1234Ser (c.3700C>T) in the general population?

CACHD1 p.Pro1234Ser (c.3700C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CACHD1 p.Pro1234Ser (c.3700C>T)?

AlphaMissense predicts ambiguous (score 0.4777) — an in-silico prediction, not a clinical call.

CACHD1 p.Pro1234Ser

c.3700C>T · VCV3994382

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4777 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4777	ambiguous
REVEL	0.201	benign-leaning
SaProt	LLR -5.89	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 171 bp · p 0.9 · regional, not allelic
Overall
CADD	22.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CACHD1
Protein: p.Pro1234Ser
Coding: c.3700C>T
MANE Select: NM_020925
Type: single nucleotide variant
Location: chr1:64691436 (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-pro1234ser (accessed [today's date]).

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