Is DAD1 p.Cys45Arg (c.133T>C) pathogenic?

DAD1 p.Cys45Arg (c.133T>C) is classified Uncertain significance in DAD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-08). AlphaMissense: likely pathogenic (0.9791); Very rare (popmax 0.00267%, afr).

How common is DAD1 p.Cys45Arg (c.133T>C) in the general population?

DAD1 p.Cys45Arg (c.133T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about DAD1 p.Cys45Arg (c.133T>C)?

AlphaMissense predicts likely pathogenic (score 0.9791) — an in-silico prediction, not a clinical call.

DAD1 p.Cys45Arg

c.133T>C · VCV4009283

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9791 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9791	likely pathogenic
REVEL	0.577	indeterminate
SaProt	LLR -14.53	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 14 kb · p 0.12 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00267% African / African-American · 2/74,942 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,614,122 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,471
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: DAD1
Protein: p.Cys45Arg
Coding: c.133T>C
MANE Select: NM_001344
Type: single nucleotide variant
Location: chr14:22589025 (GRCh38)
Gene constraint: LOEUF 0.958 · pLI 0.29 (gnomAD)
Structure: AlphaFold pLDDT 95.43 · 6 PDB
Residue 45: an α-helix

Full DAD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DAD1 c.212-128T>C Benign ★★ same type
DAD1 c.*44+172T>C Benign ★★ same type
DAD1 c.*44+72A>T Benign ★★ same type
DAD1 p.Ter114= Benign ★★ same type
DAD1 p.Ala93Asp Uncertain significance ★ ⚠ same type
DAD1 p.Ala93Gly Uncertain significance ★ ⚠ same type
DAD1 p.Asn54Lys Uncertain significance ★ ⚠ same type
DAD1 p.Gln22Arg 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/dad1-p-cys45arg (accessed [today's date]).

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