Is AFF4 p.Thr136Pro (c.406A>C) pathogenic?

AFF4 p.Thr136Pro (c.406A>C) is classified Benign in AFF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0728); Low-frequency (popmax 3.49%, afr); Associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome.

How common is AFF4 p.Thr136Pro (c.406A>C) in the general population?

AFF4 p.Thr136Pro (c.406A>C) is low-frequency (popmax 3.49%, afr) (gnomAD).

What do computational predictors say about AFF4 p.Thr136Pro (c.406A>C)?

AlphaMissense predicts likely benign (score 0.0728) — an in-silico prediction, not a clinical call.

AFF4 p.Thr136Pro

Q: What condition is associated with AFF4 p.Thr136Pro (c.406A>C)?

AFF4 p.Thr136Pro (c.406A>C) is associated with cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome (ClinVar).

c.406A>C · rs34527550 · VCV707492

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0728 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.49%, afr)

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	0.0728	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -6.16	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 1.4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 477 bp · p 0.29 · regional, not allelic
Overall
CADD	18.74	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 3.49% African / African-American · 2,617/75,022 alleles

Filtering AF 3.38% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.33%

Overall 0.192% 3,101/1,614,142 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.49%	29
Middle Eastern	0.346%	289
Remaining individualsnot grpmax-eligible	0.248%	403
Admixed American	0.203%	492
European (non-Finnish)	0.0151%	6,629
South Asian	0.00878%	11,386

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.Thr136Pro
Coding: c.406A>C
MANE Select: NM_014423
dbSNP: rs34527550
Type: single nucleotide variant
Location: chr5:132934659 (GRCh38)
Gene constraint: LOEUF 0.114 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 54.62 · 9 PDB
Residue 136: the 'disordered' region; a UniProt-annotated variant site (in)

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-thr136pro (accessed [today's date]).

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