Is ADGRF5 p.Phe76Ser (c.227T>C) pathogenic?

ADGRF5 p.Phe76Ser (c.227T>C) is classified Uncertain significance in ADGRF5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: likely benign (0.2366); Ultra-rare (popmax 0.0318%, sas).

How common is ADGRF5 p.Phe76Ser (c.227T>C) in the general population?

ADGRF5 p.Phe76Ser (c.227T>C) is ultra-rare (popmax 0.0318%, sas) (gnomAD).

What do computational predictors say about ADGRF5 p.Phe76Ser (c.227T>C)?

AlphaMissense predicts likely benign (score 0.2366) — an in-silico prediction, not a clinical call.

ADGRF5 p.Phe76Ser

c.227T>C · VCV4240640

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2366 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0318%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2366	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -5.55	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 3	GERP -2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 46 kb · p 0.61 · regional, not allelic
Overall
CADD	18.71	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 0.0318% South Asian · 29/91,052 alleles

Filtering AF 0.0228% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0196%

Overall 0.00254% 41/1,611,808 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0318%	3,140
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.00801%	12,482
European (non-Finnish)	0.000509%	196,309

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.Phe76Ser
Coding: c.227T>C
MANE Select: NM_001098518
Type: single nucleotide variant
Location: chr6:46888436 (GRCh38)
Gene constraint: LOEUF 0.719 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.74

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-phe76ser (accessed [today's date]).

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