Is AFP p.Ser445= (c.1335G>A) pathogenic?

AFP p.Ser445= (c.1335G>A) is classified Benign in AFP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-08-20). Common (popmax 9.77%, afr) — too common for a highly-penetrant pathogenic allele.

AFP p.Ser445=

Q: How common is AFP p.Ser445= (c.1335G>A) in the general population?

AFP p.Ser445= (c.1335G>A) is common (popmax 9.77%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1335G>A · rs1894264 · VCV780929

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 9.77%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12	GERP -3.7
Overall
CADD	0.116	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.77% African / African-American · 7,330/74,994 alleles

Filtering AF 9.59% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.51%

Overall 0.515% 8,319/1,614,072 alleles · common exomes 4,088/1,461,852 · genomes 4,231/152,220 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	9.77%	10
Remaining individualsnot grpmax-eligible	0.646%	155
Admixed American	0.625%	160
Middle Eastern	0.528%	189
South Asian	0.034%	2,938
European (non-Finnish)	0.0123%	8,138
East Asian	0.00446%	22,438

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: AFP
Protein: p.Ser445=
Coding: c.1335G>A
MANE Select: NM_001134
dbSNP: rs1894264
Type: single nucleotide variant
Location: chr4:73450660 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.83 · 5 PDB
Residue 445: a modified residue (phosphoserine; by fam20c); the albumin 3 domain; an α-helix

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

Similar variants

AFP p.Ser445Leu Uncertain significance ★ ⚠ same residue
AFP c.714-5C>T Likely benign ★★ same type
AFP p.Ser286= Benign ★★ same type
AFP p.Gly608Arg Likely pathogenic ★ ⚠ same type
AFP p.Ala134Val Uncertain significance ★ ⚠ same type
AFP p.Ala471Val Uncertain significance ★ ⚠ same type
AFP p.Ala476Thr Uncertain significance ★ ⚠ same type
AFP p.Ala476Val 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/afp-p-ser445 (accessed [today's date]).

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