Is ADGRF3 p.Pro156Ser (c.466C>T) pathogenic?

ADGRF3 p.Pro156Ser (c.466C>T) is classified Uncertain significance in ADGRF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-17). AlphaMissense: likely benign (0.107); Ultra-rare (popmax 0.0216%, amr).

How common is ADGRF3 p.Pro156Ser (c.466C>T) in the general population?

ADGRF3 p.Pro156Ser (c.466C>T) is ultra-rare (popmax 0.0216%, amr) (gnomAD).

What do computational predictors say about ADGRF3 p.Pro156Ser (c.466C>T)?

AlphaMissense predicts likely benign (score 0.107) — an in-silico prediction, not a clinical call.

ADGRF3 p.Pro156Ser

c.466C>T · VCV4240213

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.107 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0216%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.107	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -7.35	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 -1.8	GERP -2.1
Regional constraint	o/e 0.90	unconstrained · MANE · 37 kb · p 0.0006 · regional, not allelic
Overall
CADD	0.114	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P215S vs ClinVar P156S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0216% Admixed American · 11/50,976 alleles

Filtering AF 0.012% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00932%

Overall 0.00116% 18/1,551,700 alleles · ultra-rare exomes 7/1,399,438 · genomes 11/152,262 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0216%	4,634
European (non-Finnish)	0.00061%	163,855

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: ADGRF3
Protein: p.Pro156Ser
Coding: c.466C>T
MANE Select: NM_001321971
Type: single nucleotide variant
Location: chr2:26316308 (GRCh38)
Gene constraint: LOEUF 1.069 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.07

Full ADGRF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADGRF3 c.115-1315G>A Uncertain significance ★ ⚠ same type
ADGRF3 c.115-1349C>A Uncertain significance ★ ⚠ same type
ADGRF3 c.115-1360G>A Uncertain significance ★ ⚠ same type
ADGRF3 c.115-1415G>A Uncertain significance ★ ⚠ same type
ADGRF3 c.115-1448A>G Uncertain significance ★ ⚠ same type
ADGRF3 c.115-1453C>T Uncertain significance ★ ⚠ same type
ADGRF3 c.115-1477C>T Uncertain significance ★ ⚠ same type
ADGRF3 c.115-1480G>A 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/adgrf3-p-pro156ser (accessed [today's date]).

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