Is AFM p.Phe356Leu (c.1068T>G) pathogenic?

AFM p.Phe356Leu (c.1068T>G) is classified Uncertain significance in AFM (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-22). AlphaMissense: likely pathogenic (0.7242); Ultra-rare (popmax 0.0747%, amr).

How common is AFM p.Phe356Leu (c.1068T>G) in the general population?

AFM p.Phe356Leu (c.1068T>G) is ultra-rare (popmax 0.0747%, amr) (gnomAD).

What do computational predictors say about AFM p.Phe356Leu (c.1068T>G)?

AlphaMissense predicts likely pathogenic (score 0.7242) — an in-silico prediction, not a clinical call.

AFM p.Phe356Leu

c.1068T>G · rs759368825 · VCV2343439

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7242 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0747%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7242	likely pathogenic · top 7% in AFM
REVEL	0.278	benign-leaning
SaProt	LLR -8.82	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.33	GERP 1.7, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 21 kb · p 0.0081 · regional, not allelic
Overall
CADD	19.26	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

Grpmax group 0.0747% Admixed American · 36/48,216 alleles

Filtering AF 0.0554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0487%

Overall 0.00234% 37/1,579,676 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0747%	1,339
Remaining individualsnot grpmax-eligible	0.00164%	61,074

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.Phe356Leu
Coding: c.1068T>G
MANE Select: NM_001133
dbSNP: rs759368825
Type: single nucleotide variant
Location: chr4:73495309 (GRCh38)
Gene constraint: LOEUF 1.44 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.47 · 3 PDB
Residue 356: a disulfide bond; the albumin 2 domain; an α-helix

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-phe356leu (accessed [today's date]).

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