Is CACFD1 p.Ser34Cys (c.101C>G) pathogenic?

CACFD1 p.Ser34Cys (c.101C>G) is classified Uncertain significance in CACFD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-24). AlphaMissense: likely benign (0.1018); Very rare (popmax 0.000522%, nfe).

How common is CACFD1 p.Ser34Cys (c.101C>G) in the general population?

CACFD1 p.Ser34Cys (c.101C>G) is very rare (popmax 0.000522%, nfe) (gnomAD).

What do computational predictors say about CACFD1 p.Ser34Cys (c.101C>G)?

AlphaMissense predicts likely benign (score 0.1018) — an in-silico prediction, not a clinical call.

CACFD1 p.Ser34Cys

c.101C>G · rs372774526 · VCV2550987

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1018 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000522%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1018	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -5.68	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 7.3	GERP 1.6, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 8,583 bp · p 0.061 · regional, not allelic
Overall
CADD	25.3	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 0.000522% European (non-Finnish) · 6/1,149,924 alleles

Filtering AF 0.000188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000123%

Overall 0.000428% 6/1,402,940 alleles · very rare

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.Ser34Cys
Coding: c.101C>G
MANE Select: NM_017586
dbSNP: rs372774526
Type: single nucleotide variant
Location: chr9:133460167 (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-ser34cys (accessed [today's date]).

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