Is CACHD1 p.Val273Ile (c.817G>A) pathogenic?

CACHD1 p.Val273Ile (c.817G>A) is classified Uncertain significance in CACHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: likely benign (0.0865); Ultra-rare (popmax 0.0137%, afr); Associated with Inborn genetic diseases.

What condition is associated with CACHD1 p.Val273Ile (c.817G>A)?

CACHD1 p.Val273Ile (c.817G>A) is associated with Inborn genetic diseases (ClinVar).

How common is CACHD1 p.Val273Ile (c.817G>A) in the general population?

CACHD1 p.Val273Ile (c.817G>A) is ultra-rare (popmax 0.0137%, afr) (gnomAD).

What do computational predictors say about CACHD1 p.Val273Ile (c.817G>A)?

AlphaMissense predicts likely benign (score 0.0865) — an in-silico prediction, not a clinical call.

CACHD1 p.Val273Ile

c.817G>A · rs530434842 · VCV3136294

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0865 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0137%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0865	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -9.66	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 8.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 203 kb · p 0.00059 · regional, not allelic
Overall
CADD	21.7	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 0.0137% African / African-American · 10/73,232 alleles

Filtering AF 0.00738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00561%

Overall 0.00249% 40/1,605,916 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0145%	6,920
African / African-Americangrpmax	0.0137%	7,323
South Asian	0.00882%	11,336
Ashkenazi Jewishnot grpmax-eligible	0.00679%	14,738
Admixed American	0.00338%	29,549
European (non-Finnish)	0.000765%	130,784

Remaining individuals 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: CACHD1
Protein: p.Val273Ile
Coding: c.817G>A
MANE Select: NM_020925
dbSNP: rs530434842
Type: single nucleotide variant
Location: chr1:64634071 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.76
Residue 273: the vwfa domain

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-val273ile (accessed [today's date]).

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