Is AFF1 p.Pro348Ser (c.1042C>T) pathogenic?

AFF1 p.Pro348Ser (c.1042C>T) is classified Uncertain significance in AFF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-05). AlphaMissense: likely benign (0.2058); Ultra-rare (popmax 0.02%, eas).

How common is AFF1 p.Pro348Ser (c.1042C>T) in the general population?

AFF1 p.Pro348Ser (c.1042C>T) is ultra-rare (popmax 0.02%, eas) (gnomAD).

What do computational predictors say about AFF1 p.Pro348Ser (c.1042C>T)?

AlphaMissense predicts likely benign (score 0.2058) — an in-silico prediction, not a clinical call.

AFF1 p.Pro348Ser

c.1042C>T · rs374948523 · VCV3092130

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2058 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2058	likely benign
REVEL	0.535	indeterminate
SaProt	LLR -6.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.4, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 84 kb · p 0.031 · regional, not allelic
Overall
CADD	23.8	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 P341S vs ClinVar P348S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% East Asian · 9/44,892 alleles

Filtering AF 0.0104% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00779%

Overall 0.00347% 56/1,614,042 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0608%	1,644
East Asiangrpmax	0.02%	4,988
African / African-American	0.00801%	12,485
Admixed American	0.00333%	30,001
European (non-Finnish)	8.47e-05%	1,180,034

Remaining individuals 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.Pro348Ser
Coding: c.1042C>T
MANE Select: NM_001166693
dbSNP: rs374948523
Type: single nucleotide variant
Location: chr4:87047577 (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 p.Pro348Ala Uncertain significance ★ ⚠ same residue
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

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-pro348ser (accessed [today's date]).

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