Is AIFM2 p.Ser331Pro (c.991T>C) pathogenic?

AIFM2 p.Ser331Pro (c.991T>C) is classified Uncertain significance in AIFM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: ambiguous (0.3684); Absent from gnomAD v4.1.

How common is AIFM2 p.Ser331Pro (c.991T>C) in the general population?

AIFM2 p.Ser331Pro (c.991T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AIFM2 p.Ser331Pro (c.991T>C)?

AlphaMissense predicts ambiguous (score 0.3684) — an in-silico prediction, not a clinical call.

AIFM2 p.Ser331Pro

c.991T>C · VCV4028991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3684 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3684	ambiguous
REVEL	0.23	benign-leaning
SaProt	LLR -7.47	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 9,903 bp · p 0.49 · regional, not allelic
Overall
CADD	21.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AIFM2
Protein: p.Ser331Pro
Coding: c.991T>C
MANE Select: NM_032797
Type: single nucleotide variant
Location: chr10:70114309 (GRCh38)
Gene constraint: LOEUF 1.404 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.79 · 6 PDB
Residue 331: a β-strand

Full AIFM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AIFM2 p.Ala11Thr Uncertain significance ★ ⚠ same type
AIFM2 p.Ala25Thr Uncertain significance ★ ⚠ same type
AIFM2 p.Ala27Thr Uncertain significance ★ ⚠ same type
AIFM2 p.Ala287Thr Uncertain significance ★ ⚠ same type
AIFM2 p.Ala305Thr Uncertain significance ★ ⚠ same type
AIFM2 p.Ala307Val Uncertain significance ★ ⚠ same type
AIFM2 p.Ala325Thr Uncertain significance ★ ⚠ same type
AIFM2 p.Ala32Ser 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/aifm2-p-ser331pro (accessed [today's date]).

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