Is AFP p.Thr547= (c.1641A>G) pathogenic?

AFP p.Thr547= (c.1641A>G) is classified Benign in AFP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-27). Common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Alpha-fetoprotein deficiency.

What condition is associated with AFP p.Thr547= (c.1641A>G)?

AFP p.Thr547= (c.1641A>G) is associated with Alpha-fetoprotein deficiency (ClinVar).

AFP p.Thr547=

Q: How common is AFP p.Thr547= (c.1641A>G) in the general population?

AFP p.Thr547= (c.1641A>G) is common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1641A>G · VCV3338239

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 100%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

Alpha-fetoprotein deficiency

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 -2.6	GERP -3.7
Overall
CADD	0.076	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 100% East Asian · 44,857/44,858 alleles

Filtering AF 99.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 99.8%

Overall 99.6% 1,606,186/1,611,926 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	100%	1
Ashkenazi Jewishnot grpmax-eligible	100%	1
Amishnot grpmax-eligible	100%	1
East Asiangrpmax	100%	1
European (non-Finnish)	100%	1
South Asian	100%	1
Middle Eastern	99.8%	1
Remaining individualsnot grpmax-eligible	99.5%	1
Admixed American	99.5%	1
African / African-American	93.3%	1

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr547=
Coding: c.1641A>G
MANE Select: NM_001134
Type: single nucleotide variant
Location: chr4:73452613 (GRCh38)
Gene constraint: LOEUF 0.963 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.83 · 5 PDB
Residue 547: a disulfide bond; the albumin 3 domain; an α-helix

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

Disease context

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

Similar variants

AFP p.Thr547Ile Benign same residue
AFP p.Trp181Ter Pathogenic same condition
AFP p.Leu295fs Pathogenic 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
AFP p.Ala134Val 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-thr547 (accessed [today's date]).

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