Is AFP p.Leu260Val (c.778C>G) pathogenic?

AFP p.Leu260Val (c.778C>G) is classified Uncertain significance in AFP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-21). AlphaMissense: likely benign (0.078); Rare (popmax 0.778%, eas); Associated with Alpha-fetoprotein, hereditary persistence of.

What condition is associated with AFP p.Leu260Val (c.778C>G)?

AFP p.Leu260Val (c.778C>G) is associated with Alpha-fetoprotein, hereditary persistence of (ClinVar).

How common is AFP p.Leu260Val (c.778C>G) in the general population?

AFP p.Leu260Val (c.778C>G) is rare (popmax 0.778%, eas) (gnomAD).

What do computational predictors say about AFP p.Leu260Val (c.778C>G)?

AlphaMissense predicts likely benign (score 0.078) — an in-silico prediction, not a clinical call.

AFP p.Leu260Val

c.778C>G · VCV3779251

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.078 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.778%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Alpha-fetoprotein, hereditary persistence of

Computational evidence

Protein change
AlphaMissense	0.078	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -4.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.46	GERP -0.83
Regional constraint	o/e 0.98	unconstrained · MANE · 19 kb · p 0.58 · regional, not allelic
Overall
CADD	6.483	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.778% East Asian · 349/44,856 alleles

Filtering AF 0.711% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.684%

Overall 0.0222% 358/1,613,824 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.778%	129
Remaining individualsnot grpmax-eligible	0.008%	12,499
South Asian	0.0022%	45,534
Admixed American	0.00167%	60,008
European (non-Finnish)	8.48e-05%	1,179,848

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.Leu260Val
Coding: c.778C>G
MANE Select: NM_001134
Type: single nucleotide variant
Location: chr4:73445057 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.83 · 5 PDB
Residue 260: a disulfide bond; the albumin 2 domain; an α-helix

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

Disease context

Alpha-fetoprotein, hereditary persistence of — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AFP p.His22Asn Uncertain significance ★ ⚠ same condition
AFP p.Thr253Ser Uncertain significance ★ ⚠ same condition
AFP c.*10+2T>C Likely benign ★ same condition
AFP p.Lys322_Pro323delinsAsn Uncertain significance ★ same condition
AFP c.714-5C>T Likely benign ★★ same type
AFP p.Ser286= Benign ★★ same type
AFP p.Ser445= Benign ★★ same type
AFP p.Gly608Arg Likely pathogenic ★ ⚠ 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-leu260val (accessed [today's date]).

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