Is DCAF8 p.Ala146Val (c.437C>T) pathogenic?

DCAF8 p.Ala146Val (c.437C>T) is classified Uncertain significance in DCAF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-01). AlphaMissense: likely benign (0.0778); Very rare (popmax 0.000339%, nfe).

How common is DCAF8 p.Ala146Val (c.437C>T) in the general population?

DCAF8 p.Ala146Val (c.437C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about DCAF8 p.Ala146Val (c.437C>T)?

AlphaMissense predicts likely benign (score 0.0778) — an in-silico prediction, not a clinical call.

DCAF8 p.Ala146Val

c.437C>T · rs2525192257 · VCV1711231

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0778 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0778	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -7.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.67 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 0.7, phastCons 1
Regional constraint	o/e 0.53	unconstrained · MANE · 15 kb · p 9.7e-17 · regional, not allelic
Overall
CADD	22.0	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 0.000339% European (non-Finnish) · 4/1,180,048 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,892 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: DCAF8
Protein: p.Ala146Val
Coding: c.437C>T
MANE Select: NM_015726
dbSNP: rs2525192257
Type: single nucleotide variant
Location: chr1:160239983 (GRCh38)
Gene constraint: LOEUF 0.466 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.60 · 2 PDB
Residue 146: the 'disordered' region

Full DCAF8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DCAF8 p.Ala146Pro Uncertain significance ★ ⚠ same residue
DCAF8 p.Arg117Cys Uncertain significance ★★ ⚠ same type
DCAF8 p.Arg122Trp Uncertain significance ★★ ⚠ same type
DCAF8 p.Asn343Ser Uncertain significance ★★ ⚠ same type
DCAF8 p.Ser419Asn Uncertain significance ★★ ⚠ same type
DCAF8 p.Ser576Pro Uncertain significance ★★ ⚠ same type
DCAF8 p.Arg204= Benign/Likely benign ★★ same type
DCAF8 p.Arg263= Benign ★★ 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/dcaf8-p-ala146val (accessed [today's date]).

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