Is CACFD1 p.Ala76Val (c.227C>T) pathogenic?

CACFD1 p.Ala76Val (c.227C>T) is classified Uncertain significance in CACFD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely benign (0.0594); Ultra-rare (popmax 0.0187%, sas).

How common is CACFD1 p.Ala76Val (c.227C>T) in the general population?

CACFD1 p.Ala76Val (c.227C>T) is ultra-rare (popmax 0.0187%, sas) (gnomAD).

What do computational predictors say about CACFD1 p.Ala76Val (c.227C>T)?

AlphaMissense predicts likely benign (score 0.0594) — an in-silico prediction, not a clinical call.

CACFD1 p.Ala76Val

c.227C>T · rs369686686 · VCV2469997

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0594 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0594	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -4.43	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 0.077	GERP -1.7, phastCons 0.002
Regional constraint	o/e 1.12	unconstrained · MANE · 8,583 bp · p 0.061 · regional, not allelic
Overall
CADD	18.33	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 0.0187% South Asian · 17/91,088 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.00991% 160/1,613,872 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0188%	5,332
South Asiangrpmax	0.0187%	5,358
European (non-Finnish)	0.0106%	9,440
African / African-American	0.00401%	24,969
Remaining individualsnot grpmax-eligible	0.0032%	31,240
Admixed American	0.00167%	59,992

Finnish 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: CACFD1
Protein: p.Ala76Val
Coding: c.227C>T
MANE Select: NM_017586
dbSNP: rs369686686
Type: single nucleotide variant
Location: chr9:133465354 (GRCh38)
Gene constraint: LOEUF 1.857 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.71

Full CACFD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CACFD1 c.429-111A>G Uncertain significance ★ same type
CACFD1 c.429-158G>A Uncertain significance ★ same type
CACFD1 c.429-159G>C Uncertain significance ★ same type
CACFD1 c.429-195G>A Uncertain significance ★ same type
CACFD1 c.429-197C>A Uncertain significance ★ same type
CACFD1 c.*12C>T Uncertain significance ★ same type
CACFD1 c.*30C>T Uncertain significance ★ same type
CACFD1 c.*45G>A 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/cacfd1-p-ala76val (accessed [today's date]).

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