Is AFM p.Leu258Pro (c.773T>C) pathogenic?

AFM p.Leu258Pro (c.773T>C) is classified Uncertain significance in AFM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely pathogenic (0.7988); Very rare (popmax 0.0022%, sas).

How common is AFM p.Leu258Pro (c.773T>C) in the general population?

AFM p.Leu258Pro (c.773T>C) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about AFM p.Leu258Pro (c.773T>C)?

AlphaMissense predicts likely pathogenic (score 0.7988) — an in-silico prediction, not a clinical call.

AFM p.Leu258Pro

c.773T>C · rs139224995 · VCV2482591

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7988 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7988	likely pathogenic · top 4% in AFM
REVEL	0.65	pathogenic-leaning
SaProt	LLR -16.60	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.57	acceptor loss, 6 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.2	GERP 0.2, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 21 kb · p 0.0081 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/90,972 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000753% 11/1,460,886 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,486
European (non-Finnish)	0.000763%	131,045

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: AFM
Protein: p.Leu258Pro
Coding: c.773T>C
MANE Select: NM_001133
dbSNP: rs139224995
Type: single nucleotide variant
Location: chr4:73488689 (GRCh38)
Gene constraint: LOEUF 1.44 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.47 · 3 PDB
Residue 258: a disulfide bond; the albumin 2 domain; an α-helix; the 'binding pocket for hydrophobic ligands' region

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

Similar variants

AFM p.Ala100Val Uncertain significance ★ ⚠ same type
AFM p.Ala150Pro Uncertain significance ★ ⚠ same type
AFM p.Ala241Val Uncertain significance ★ ⚠ same type
AFM p.Ala352Glu Uncertain significance ★ ⚠ same type
AFM p.Ala352Val Uncertain significance ★ ⚠ same type
AFM p.Ala397Thr Uncertain significance ★ ⚠ same type
AFM p.Ala397Val Uncertain significance ★ ⚠ same type
AFM p.Ala439Pro 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/afm-p-leu258pro (accessed [today's date]).

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