Is PHF20 p.Arg654Pro (c.1961G>C) pathogenic?

PHF20 p.Arg654Pro (c.1961G>C) is classified Uncertain significance in PHF20 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: likely pathogenic (0.9878); Absent from gnomAD v4.1.

How common is PHF20 p.Arg654Pro (c.1961G>C) in the general population?

PHF20 p.Arg654Pro (c.1961G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHF20 p.Arg654Pro (c.1961G>C)?

AlphaMissense predicts likely pathogenic (score 0.9878) — an in-silico prediction, not a clinical call.

PHF20 p.Arg654Pro

c.1961G>C · VCV4135689

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9878 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9878	likely pathogenic · top 7% in PHF20
REVEL	0.712	pathogenic-leaning
SaProt	LLR -17.90	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 116 kb · p 3.5e-12 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PHF20
Protein: p.Arg654Pro
Coding: c.1961G>C
MANE Select: NM_016436
Type: single nucleotide variant
Location: chr20:35917619 (GRCh38)
Gene constraint: LOEUF 0.249 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 55.32 · 7 PDB

Full PHF20 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PHF20 c.1826-4G>A Benign ★★ same type
PHF20 c.2897-6C>T Benign/Likely benign ★★ same type
PHF20 p.Arg845= Benign ★★ same type
PHF20 p.Phe621= Benign ★★ same type
PHF20 p.Pro827= Benign ★★ same type
PHF20 p.Ala235Asp Uncertain significance ★ ⚠ same type
PHF20 p.Ala395Val Uncertain significance ★ ⚠ same type
PHF20 p.Ala443Thr 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/phf20-p-arg654pro (accessed [today's date]).

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