Is ADGRF4 p.Pro65Ser (c.193C>T) pathogenic?

ADGRF4 p.Pro65Ser (c.193C>T) is classified Uncertain significance in ADGRF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-26). AlphaMissense: likely benign (0.0765); Very rare (popmax 0.00119%, nfe).

How common is ADGRF4 p.Pro65Ser (c.193C>T) in the general population?

ADGRF4 p.Pro65Ser (c.193C>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

What do computational predictors say about ADGRF4 p.Pro65Ser (c.193C>T)?

AlphaMissense predicts likely benign (score 0.0765) — an in-silico prediction, not a clinical call.

ADGRF4 p.Pro65Ser

c.193C>T · VCV3498203

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0765 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0765	likely benign
REVEL	0.011	strongly benign-leaning
SaProt	LLR -8.61	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 0.38	GERP -1.9
Regional constraint	o/e 1.10	unconstrained · MANE · 11 kb · p 0.0027 · regional, not allelic
Overall
CADD	3.788	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 0.00119% European (non-Finnish) · 14/1,179,262 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000868% 14/1,612,446 alleles · very rare exomes 12/1,460,324 · genomes 2/152,122 · joint denominator

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: ADGRF4
Protein: p.Pro65Ser
Coding: c.193C>T
MANE Select: NM_153838
Type: single nucleotide variant
Location: chr6:47710779 (GRCh38)
Gene constraint: LOEUF 1.36 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.70

Full ADGRF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADGRF4 p.Ala197Thr Uncertain significance ★ ⚠ same type
ADGRF4 p.Ala198Asp Uncertain significance ★ ⚠ same type
ADGRF4 p.Ala495Thr Uncertain significance ★ same type
ADGRF4 p.Ala561Thr Uncertain significance ★ same type
ADGRF4 p.Ala680Pro Uncertain significance ★ ⚠ same type
ADGRF4 p.Ala680Ser Uncertain significance ★ ⚠ same type
ADGRF4 p.Arg107His Uncertain significance ★ ⚠ same type
ADGRF4 p.Arg136Cys 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/adgrf4-p-pro65ser (accessed [today's date]).

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