Is AFF4 p.Pro83Thr (c.247C>A) pathogenic?

AFF4 p.Pro83Thr (c.247C>A) is classified Uncertain significance in AFF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-02). AlphaMissense: likely benign (0.054); Absent from gnomAD v4.1; Associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome.

How common is AFF4 p.Pro83Thr (c.247C>A) in the general population?

AFF4 p.Pro83Thr (c.247C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AFF4 p.Pro83Thr (c.247C>A)?

AlphaMissense predicts likely benign (score 0.054) — an in-silico prediction, not a clinical call.

AFF4 p.Pro83Thr

Q: What condition is associated with AFF4 p.Pro83Thr (c.247C>A)?

AFF4 p.Pro83Thr (c.247C>A) is associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome (ClinVar).

c.247C>A · rs2532577283 · VCV2842267

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.054 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.054	likely benign
REVEL	0.512	indeterminate
SaProt	LLR -7.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 4.1, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 2,298 bp · p 2e-05 · regional, not allelic
Overall
CADD	26.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AFF4
Protein: p.Pro83Thr
Coding: c.247C>A
MANE Select: NM_014423
dbSNP: rs2532577283
Type: single nucleotide variant
Location: chr5:132934818 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 83: the 'disordered' region

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

Disease context

cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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
AFF4 p.Ala114Val Uncertain significance ★★ ⚠ same condition
AFF4 p.Ala27Thr 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-pro83thr (accessed [today's date]).

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