Is AFF1 p.Gln350Pro (c.1049A>C) pathogenic?

AFF1 p.Gln350Pro (c.1049A>C) is classified Uncertain significance in AFF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely benign (0.0811); Rare (popmax 0.257%, afr).

How common is AFF1 p.Gln350Pro (c.1049A>C) in the general population?

AFF1 p.Gln350Pro (c.1049A>C) is rare (popmax 0.257%, afr) (gnomAD).

What do computational predictors say about AFF1 p.Gln350Pro (c.1049A>C)?

AlphaMissense predicts likely benign (score 0.0811) — an in-silico prediction, not a clinical call.

AFF1 p.Gln350Pro

c.1049A>C · VCV4638752

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0811 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.257%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0811	likely benign
REVEL	0.535	indeterminate
SaProt	LLR -5.06	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.73 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 1.3, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 84 kb · p 0.031 · regional, not allelic
Overall
CADD	22.8	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM Q343P vs ClinVar Q350P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.257% African / African-American · 193/75,060 alleles

Filtering AF 0.227% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.216%

Overall 0.0135% 218/1,614,176 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.257%	389
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0224%	4,465
Admixed American	0.01%	10,004
European (non-Finnish)	0.000254%	393,342

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: AFF1
Protein: p.Gln350Pro
Coding: c.1049A>C
MANE Select: NM_001166693
Type: single nucleotide variant
Location: chr4:87047584 (GRCh38)
Gene constraint: LOEUF 0.49 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 53.06 · 1 PDB

Full AFF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AFF1 c.1191+8C>T Benign/Likely benign ★★ same type
AFF1 p.Ala40= Benign ★★ same type
AFF1 p.Pro393= Benign ★★ same type
AFF1 p.Ser627Cys Likely benign ★★ ⚠ same type
AFF1 p.Thr426= Likely benign ★★ same type
AFF1 p.Val711Ile Benign ★★ same type
AFF1 p.Ala1047Val Uncertain significance ★ ⚠ same type
AFF1 p.Ala1103Thr Uncertain significance ★ ⚠ 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/aff1-p-gln350pro (accessed [today's date]).

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