Is AFF4 p.Pro890Leu (c.2669C>T) pathogenic?

AFF4 p.Pro890Leu (c.2669C>T) is classified Likely benign in AFF4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.0589); Ultra-rare (popmax 0.0194%, nfe); Associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome.

How common is AFF4 p.Pro890Leu (c.2669C>T) in the general population?

AFF4 p.Pro890Leu (c.2669C>T) is ultra-rare (popmax 0.0194%, nfe) (gnomAD).

What do computational predictors say about AFF4 p.Pro890Leu (c.2669C>T)?

AlphaMissense predicts likely benign (score 0.0589) — an in-silico prediction, not a clinical call.

AFF4 p.Pro890Leu

Q: What condition is associated with AFF4 p.Pro890Leu (c.2669C>T)?

AFF4 p.Pro890Leu (c.2669C>T) is associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome (ClinVar).

c.2669C>T · rs200457433 · VCV772457

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0589 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0194%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

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

Computational evidence

Protein change
AlphaMissense	0.0589	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -7.08	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 12	GERP 5.4, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 7,535 bp · p 0.44 · regional, not allelic
Overall
CADD	25.0	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 0.0194% European (non-Finnish) · 229/1,179,874 alleles

Filtering AF 0.0173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0165%

Overall 0.0181% 292/1,613,928 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.075%	1,333
European (non-Finnish)grpmax	0.0194%	5,152
Admixed American	0.0117%	8,573
African / African-American	0.00666%	15,006
Remaining individualsnot grpmax-eligible	0.0048%	20,835

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro890Leu
Coding: c.2669C>T
MANE Select: NM_014423
dbSNP: rs200457433
Type: single nucleotide variant
Location: chr5:132889142 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 890: 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-pro890leu (accessed [today's date]).

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