Is ADGRF5 p.Ile412Phe (c.1234A>T) pathogenic?

ADGRF5 p.Ile412Phe (c.1234A>T) is classified Uncertain significance in ADGRF5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). AlphaMissense: likely benign (0.1417); Very rare (popmax 8.53e-05%, nfe).

How common is ADGRF5 p.Ile412Phe (c.1234A>T) in the general population?

ADGRF5 p.Ile412Phe (c.1234A>T) is very rare (popmax 8.53e-05%, nfe) (gnomAD).

What do computational predictors say about ADGRF5 p.Ile412Phe (c.1234A>T)?

AlphaMissense predicts likely benign (score 0.1417) — an in-silico prediction, not a clinical call.

ADGRF5 p.Ile412Phe

c.1234A>T · VCV4240549

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1417 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.53e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1417	likely benign
REVEL	0.181	moderately benign-leaning
SaProt	LLR -7.34	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 0.69	GERP 0.84, phastCons 0.55
Regional constraint	o/e 1.02	unconstrained · MANE · 46 kb · p 0.61 · regional, not allelic
Overall
CADD	19.31	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 8.53e-05% European (non-Finnish) · 1/1,172,474 alleles

Overall 6.88e-05% 1/1,453,558 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: ADGRF5
Protein: p.Ile412Phe
Coding: c.1234A>T
MANE Select: NM_001098518
Type: single nucleotide variant
Location: chr6:46878208 (GRCh38)
Gene constraint: LOEUF 0.719 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.74
Residue 412: the ig-like 2 domain; a disulfide bond

Full ADGRF5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADGRF5 p.Ala1064Val Uncertain significance ★ ⚠ same type
ADGRF5 p.Ala1072Thr Uncertain significance ★ ⚠ same type
ADGRF5 p.Ala1072Val Uncertain significance ★ ⚠ same type
ADGRF5 p.Ala1088Ser Uncertain significance ★ ⚠ same type
ADGRF5 p.Ala1179Glu Uncertain significance ★ ⚠ same type
ADGRF5 p.Ala268Thr Uncertain significance ★ ⚠ same type
ADGRF5 p.Ala324Val Uncertain significance ★ ⚠ same type
ADGRF5 p.Ala457Thr 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/adgrf5-p-ile412phe (accessed [today's date]).

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