Is AGFG1 p.Ser447Pro (c.1339T>C) pathogenic?

AGFG1 p.Ser447Pro (c.1339T>C) is classified Uncertain significance in AGFG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-22). AlphaMissense: likely benign (0.0967); Very rare (popmax 0.000933%, nfe).

How common is AGFG1 p.Ser447Pro (c.1339T>C) in the general population?

AGFG1 p.Ser447Pro (c.1339T>C) is very rare (popmax 0.000933%, nfe) (gnomAD).

What do computational predictors say about AGFG1 p.Ser447Pro (c.1339T>C)?

AlphaMissense predicts likely benign (score 0.0967) — an in-silico prediction, not a clinical call.

AGFG1 p.Ser447Pro

c.1339T>C · rs926228180 · VCV2601146

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0967 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000933%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0967	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -9.00	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 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 29 kb · p 0.0023 · regional, not allelic
Overall
CADD	23.3	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 0.000933% European (non-Finnish) · 11/1,179,412 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000682% 11/1,613,026 alleles · very rare

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: AGFG1
Protein: p.Ser447Pro
Coding: c.1339T>C
MANE Select: NM_004504
dbSNP: rs926228180
Type: single nucleotide variant
Location: chr2:227536954 (GRCh38)
Gene constraint: LOEUF 0.286 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 57.58 · 3 PDB

Full AGFG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AGFG1 c.814+955G>A Uncertain significance ★ same type
AGFG1 p.Ala210Val Uncertain significance ★ ⚠ same type
AGFG1 p.Ala241Val Uncertain significance ★ ⚠ same type
AGFG1 p.Ala355Pro Uncertain significance ★ ⚠ same type
AGFG1 p.Ala438Gly Uncertain significance ★ ⚠ same type
AGFG1 p.Ala439Val Uncertain significance ★ ⚠ same type
AGFG1 p.Arg186Leu Uncertain significance ★ ⚠ same type
AGFG1 p.Asn228Ser 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/agfg1-p-ser447pro (accessed [today's date]).

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