Is AFF3 p.Ala712Thr (c.2134G>A) pathogenic?

AFF3 p.Ala712Thr (c.2134G>A) is classified Likely benign in AFF3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-18). AlphaMissense: likely benign (0.0655); Ultra-rare (popmax 0.0937%, nfe).

How common is AFF3 p.Ala712Thr (c.2134G>A) in the general population?

AFF3 p.Ala712Thr (c.2134G>A) is ultra-rare (popmax 0.0937%, nfe) (gnomAD).

What do computational predictors say about AFF3 p.Ala712Thr (c.2134G>A)?

AlphaMissense predicts likely benign (score 0.0655) — an in-silico prediction, not a clinical call.

AFF3 p.Ala712Thr

c.2134G>A · rs148703034 · VCV3024997

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0655 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0937%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0655	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -6.92	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 -2.1	GERP -4.7
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.083 · regional, not allelic
Overall
CADD	0.612	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 0.0937% European (non-Finnish) · 1,105/1,179,672 alleles

Filtering AF 0.089% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0872%

Overall 0.0752% 1,213/1,613,092 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.145%	688
European (non-Finnish)grpmax	0.0937%	1,068
Finnishnot grpmax-eligible	0.0378%	2,642
Remaining individualsnot grpmax-eligible	0.0352%	2,840
Admixed American	0.025%	4,001
Middle Eastern	0.0165%	6,060
African / African-American	0.004%	25,011

Ashkenazi Jewish 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: AFF3
Protein: p.Ala712Thr
Coding: c.2134G>A
MANE Select: NM_001386135
dbSNP: rs148703034
Type: single nucleotide variant
Location: chr2:99593527 (GRCh38)
Gene constraint: LOEUF 0.318 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.20
Residue 712: the 'disordered' region

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

Similar variants

AFF3 p.Ala233Thr Pathogenic ★★ ⚠ same type
AFF3 p.Ala233Val Pathogenic/Likely pathogenic ★★ ⚠ same type
AFF3 p.Ile1147Asn Uncertain significance ★★ ⚠ same type
AFF3 p.Leu370Phe Uncertain significance ★★ ⚠ same type
AFF3 p.Pro321Leu Uncertain significance ★★ ⚠ same type
AFF3 p.Ser222Thr Uncertain significance ★★ ⚠ same type
AFF3 p.Thr950Met Uncertain significance ★★ ⚠ same type
AFF3 c.1371+7G>A Likely benign ★★ same type

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-ala712thr (accessed [today's date]).

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