Is DEAF1 p.Arg451Pro (c.1352G>C) pathogenic?

DEAF1 p.Arg451Pro (c.1352G>C) is classified Uncertain significance in DEAF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). AlphaMissense: likely pathogenic (0.6211); Very rare (popmax 0.00133%, afr).

How common is DEAF1 p.Arg451Pro (c.1352G>C) in the general population?

DEAF1 p.Arg451Pro (c.1352G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about DEAF1 p.Arg451Pro (c.1352G>C)?

AlphaMissense predicts likely pathogenic (score 0.6211) — an in-silico prediction, not a clinical call.

DEAF1 p.Arg451Pro

c.1352G>C · rs757975287 · VCV1973213

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6211 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6211	likely pathogenic
REVEL	0.38	indeterminate
SaProt	LLR -6.73	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 40 kb · p 0.059 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,056 alleles

Overall 6.2e-05% 1/1,614,000 alleles · very rare exomes 1/1,461,690 · genomes 0/152,310 · joint denominator

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: DEAF1
Protein: p.Arg451Pro
Coding: c.1352G>C
MANE Select: NM_021008
dbSNP: rs757975287
Type: single nucleotide variant
Location: chr11:674687 (GRCh38)
Gene constraint: LOEUF 1.18 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.62 · 3 PDB
Residue 451: a UniProt-annotated variant site (in a primary colorectal cancer); the 'interaction with lmo4' region

Full DEAF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEAF1 p.Arg451Gln Uncertain significance ★ ⚠ same residue
DEAF1 p.Arg451= Likely benign ★ same residue
DEAF1 c.998-2A>G Likely pathogenic ★★ same type
DEAF1 p.Arg224Pro Pathogenic/Likely pathogenic ★★ same type
DEAF1 p.Arg224Trp Pathogenic/Likely pathogenic ★★ same type
DEAF1 p.Arg226Trp Pathogenic/Likely pathogenic ★★ same type
DEAF1 p.Arg246Thr Pathogenic/Likely pathogenic ★★ same type
DEAF1 p.Arg261Ter Pathogenic/Likely pathogenic ★★ 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/deaf1-p-arg451pro (accessed [today's date]).

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