Is AFF1 p.Ser951Phe (c.2852C>T) pathogenic?

AFF1 p.Ser951Phe (c.2852C>T) is classified Uncertain significance in AFF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-21). AlphaMissense: likely benign (0.215); Very rare (popmax 0.000339%, nfe).

How common is AFF1 p.Ser951Phe (c.2852C>T) in the general population?

AFF1 p.Ser951Phe (c.2852C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about AFF1 p.Ser951Phe (c.2852C>T)?

AlphaMissense predicts likely benign (score 0.215) — an in-silico prediction, not a clinical call.

AFF1 p.Ser951Phe

c.2852C>T · rs750029796 · VCV2369229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.215 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.215	likely benign
REVEL	0.267	benign-leaning
SaProt	LLR -9.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 1.3, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 84 kb · p 0.031 · regional, not allelic
Overall
CADD	22.7	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 S944F vs ClinVar S951F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,682 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00174% 28/1,612,872 alleles · very rare exomes 26/1,461,460 · genomes 2/151,412 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0744%	1,345
Remaining individualsnot grpmax-eligible	0.0032%	31,229
European (non-Finnish)grpmax	0.000339%	294,921

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: AFF1
Protein: p.Ser951Phe
Coding: c.2852C>T
MANE Select: NM_001166693
dbSNP: rs750029796
Type: single nucleotide variant
Location: chr4:87127066 (GRCh38)
Gene constraint: LOEUF 0.49 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 53.06 · 1 PDB
Residue 944 UniProt numbering: the 'disordered' region

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-ser951phe (accessed [today's date]).

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