Is AFF3 p.Ala560Ser (c.1678G>T) pathogenic?

AFF3 p.Ala560Ser (c.1678G>T) is classified Uncertain significance in AFF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-20). AlphaMissense: likely benign (0.0754); Very rare (popmax 0.00538%, sas); Associated with KINSSHIP syndrome.

What condition is associated with AFF3 p.Ala560Ser (c.1678G>T)?

AFF3 p.Ala560Ser (c.1678G>T) is associated with KINSSHIP syndrome (ClinVar).

How common is AFF3 p.Ala560Ser (c.1678G>T) in the general population?

AFF3 p.Ala560Ser (c.1678G>T) is very rare (popmax 0.00538%, sas) (gnomAD).

What do computational predictors say about AFF3 p.Ala560Ser (c.1678G>T)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

AFF3 p.Ala560Ser

c.1678G>T · VCV3341352

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00538%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

KINSSHIP syndrome

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -7.46	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 -3.1	GERP -4.2
Regional constraint	o/e 0.97	unconstrained · MANE · 413 kb · p 0.58 · regional, not allelic
Overall
CADD	1.098	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 0.00538% South Asian · 4/74,416 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00033% 5/1,516,358 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00538%	18,604
European (non-Finnish)	8.82e-05%	1,134,122

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: AFF3
Protein: p.Ala560Ser
Coding: c.1678G>T
MANE Select: NM_001386135
Type: single nucleotide variant
Location: chr2:99593983 (GRCh38)
Gene constraint: LOEUF 0.318 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.20
Residue 560: the 'disordered' region

Full AFF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

KINSSHIP syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AFF3 p.Ala233Thr Pathogenic ★★ ⚠ same condition
AFF3 p.Ala233Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
AFF3 p.Leu370Phe Uncertain significance ★★ ⚠ same condition
AFF3 p.Ser222Thr Uncertain significance ★★ ⚠ same condition
AFF3 p.Thr808Ala Likely pathogenic ★ ⚠ same condition
AFF3 c.1144-2A>G Uncertain significance ★ same condition
AFF3 c.2466+5G>A Uncertain significance ★ same condition
AFF3 c.53+41939G>A 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/aff3-p-ala560ser (accessed [today's date]).

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