Is FAP p.Arg422Gly (c.1264A>G) pathogenic?

FAP p.Arg422Gly (c.1264A>G) is classified Uncertain significance in FAP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-30). AlphaMissense: likely pathogenic (0.9534); Very rare (popmax 0.000278%, nfe).

How common is FAP p.Arg422Gly (c.1264A>G) in the general population?

FAP p.Arg422Gly (c.1264A>G) is very rare (popmax 0.000278%, nfe) (gnomAD).

What do computational predictors say about FAP p.Arg422Gly (c.1264A>G)?

AlphaMissense predicts likely pathogenic (score 0.9534) — an in-silico prediction, not a clinical call.

FAP p.Arg422Gly

c.1264A>G · VCV3848846

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9534 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000278%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9534	likely pathogenic · top 8% in FAP
REVEL	0.416	indeterminate
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 72 kb · p 0.75 · regional, not allelic
Overall
CADD	25.7	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 0.000278% European (non-Finnish) · 3/1,079,870 alleles

Filtering AF 7.4e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.1e-05%

Overall 0.000226% 3/1,328,222 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: FAP
Protein: p.Arg422Gly
Coding: c.1264A>G
MANE Select: NM_004460
Type: single nucleotide variant
Location: chr2:162200579 (GRCh38)
Gene constraint: LOEUF 0.892 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.72 · 4 PDB
Residue 422: a β-strand

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

Similar variants

FAP c.1870-8C>A Benign ★★ same type
FAP p.Ala100= Benign ★★ same type
FAP p.Gln708= Benign ★★ same type
FAP p.Gly195= Benign ★★ same type
FAP p.Leu212Phe Benign ★★ ⚠ same type
FAP p.Phe185Leu Likely benign ★★ ⚠ same type
FAP p.Ser737= Likely benign ★★ same type
FAP p.Thr229Met Benign ★★ ⚠ 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/fap-p-arg422gly (accessed [today's date]).

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