Is AFF4 p.Ile77Val (c.229A>G) pathogenic?

AFF4 p.Ile77Val (c.229A>G) is classified Uncertain significance in AFF4 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-24). AlphaMissense: likely benign (0.0835); Very rare (popmax 0.00668%, afr); Associated with AFF4-related disorder.

What condition is associated with AFF4 p.Ile77Val (c.229A>G)?

AFF4 p.Ile77Val (c.229A>G) is associated with AFF4-related disorder (ClinVar).

How common is AFF4 p.Ile77Val (c.229A>G) in the general population?

AFF4 p.Ile77Val (c.229A>G) is very rare (popmax 0.00668%, afr) (gnomAD).

What do computational predictors say about AFF4 p.Ile77Val (c.229A>G)?

AlphaMissense predicts likely benign (score 0.0835) — an in-silico prediction, not a clinical call.

AFF4 p.Ile77Val

c.229A>G · rs372069594 · VCV3035421

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0835 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AFF4-related disorder

Computational evidence

Protein change
AlphaMissense	0.0835	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -5.25	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 2.9	GERP 4.1, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 2,298 bp · p 2e-05 · regional, not allelic
Overall
CADD	18.11	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 0.00668% African / African-American · 5/74,894 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.000867% 14/1,614,000 alleles · very rare exomes 10/1,461,876 · genomes 4/152,124 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00668%	14,979
East Asian	0.00223%	44,894
South Asian	0.0022%	45,543
European (non-Finnish)	0.000508%	196,671

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.Ile77Val
Coding: c.229A>G
MANE Select: NM_014423
dbSNP: rs372069594
Type: single nucleotide variant
Location: chr5:132934836 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 77: the 'disordered' region

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

Disease context

AFF4-related disorder

Similar variants

AFF4 p.Ile77Phe Uncertain significance ★ ⚠ same residue
AFF4 p.Glu657Asp Uncertain significance ★★ ⚠ same condition
AFF4 p.Ser839Cys Uncertain significance ★★ ⚠ same condition
AFF4 p.Ala551Thr Uncertain significance ★ ⚠ same condition
AFF4 p.Arg209Ser Uncertain significance ★ ⚠ same condition
AFF4 p.Arg725Lys Uncertain significance ★ ⚠ same condition
AFF4 p.Asp422Gly Uncertain significance ★ ⚠ same condition
AFF4 p.Pro611Leu 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-ile77val (accessed [today's date]).

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