Is AFF4 p.Arg775Pro (c.2324G>C) pathogenic?

AFF4 p.Arg775Pro (c.2324G>C) is classified Uncertain significance in AFF4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-09). AlphaMissense: likely benign (0.2525); Ultra-rare (popmax 0.0461%, sas); Associated with dilated cardiomyopathy.

How common is AFF4 p.Arg775Pro (c.2324G>C) in the general population?

AFF4 p.Arg775Pro (c.2324G>C) is ultra-rare (popmax 0.0461%, sas) (gnomAD).

What do computational predictors say about AFF4 p.Arg775Pro (c.2324G>C)?

AlphaMissense predicts likely benign (score 0.2525) — an in-silico prediction, not a clinical call.

AFF4 p.Arg775Pro

Q: What condition is associated with AFF4 p.Arg775Pro (c.2324G>C)?

AFF4 p.Arg775Pro (c.2324G>C) is associated with dilated cardiomyopathy, cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome (ClinVar).

c.2324G>C · rs201192755 · VCV2438913

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2525 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0461%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dilated cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.2525	likely benign
REVEL	0.22	benign-leaning
SaProt	LLR -6.36	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 4.9	GERP 5.3, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 7,535 bp · p 0.44 · regional, not allelic
Overall
CADD	22.2	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 0.0461% South Asian · 42/91,078 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0311%

Overall 0.00304% 49/1,613,958 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0461%	2,169
Remaining individualsnot grpmax-eligible	0.0064%	15,625
Admixed American	0.00333%	30,001
East Asian	0.00223%	44,870

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: AFF4
Protein: p.Arg775Pro
Coding: c.2324G>C
MANE Select: NM_014423
dbSNP: rs201192755
Type: single nucleotide variant
Location: chr5:132893102 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 775: the 'disordered' region

Full AFF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

dilated cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome

Similar variants

AFF4 p.Arg775Ter Uncertain significance ★ same residue
AFF4 p.Arg775Gln Uncertain significance ⚠ same residue
AFF4 p.Arg258Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
AFF4 p.Met260Val Likely pathogenic ★★ ⚠ same condition
AFF4 p.Pro253Leu Pathogenic/Likely pathogenic ★★ ⚠ same condition
AFF4 p.Thr254Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
AFF4 c.1133+3A>G Uncertain significance ★★ same condition
AFF4 p.Ala114Thr Uncertain significance ★★ ⚠ same condition

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/aff4-p-arg775pro (accessed [today's date]).

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