Is AFF3 p.Asp335His (c.1003G>C) pathogenic?

AFF3 p.Asp335His (c.1003G>C) is classified Uncertain significance in AFF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-13). AlphaMissense: ambiguous (0.451); Very rare (popmax 0.00494%, nfe).

How common is AFF3 p.Asp335His (c.1003G>C) in the general population?

AFF3 p.Asp335His (c.1003G>C) is very rare (popmax 0.00494%, nfe) (gnomAD).

What do computational predictors say about AFF3 p.Asp335His (c.1003G>C)?

AlphaMissense predicts ambiguous (score 0.451) — an in-silico prediction, not a clinical call.

AFF3 p.Asp335His

c.1003G>C · VCV4853179

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.451 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00494%, nfe)

Computational evidence

Protein change
AlphaMissense	0.451	ambiguous
REVEL	0.322	indeterminate
SaProt	LLR -6.80	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.39 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 413 kb · p 0.58 · regional, not allelic
Overall
CADD	32.0	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 0.00494% European (non-Finnish) · 58/1,174,948 alleles

Filtering AF 0.00387% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00354%

Overall 0.00387% 62/1,603,240 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00494%	20,258
Remaining individualsnot grpmax-eligible	0.00483%	20,698
Admixed American	0.00172%	58,226

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.Asp335His
Coding: c.1003G>C
MANE Select: NM_001386135
Type: single nucleotide variant
Location: chr2:99744140 (GRCh38)
Gene constraint: LOEUF 0.318 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 52.20
Residue 335: 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-asp335his (accessed [today's date]).

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