Is PHF21A p.Pro545Arg (c.1634C>G) pathogenic?

PHF21A p.Pro545Arg (c.1634C>G) is classified Uncertain significance in PHF21A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-01). AlphaMissense: likely pathogenic (0.7613); Very rare (popmax 0.00017%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PHF21A p.Pro545Arg (c.1634C>G)?

PHF21A p.Pro545Arg (c.1634C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PHF21A p.Pro545Arg (c.1634C>G) in the general population?

PHF21A p.Pro545Arg (c.1634C>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about PHF21A p.Pro545Arg (c.1634C>G)?

AlphaMissense predicts likely pathogenic (score 0.7613) — an in-silico prediction, not a clinical call.

PHF21A p.Pro545Arg

c.1634C>G · VCV3931560

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7613 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7613	likely pathogenic
REVEL	0.491	indeterminate
SaProt	LLR -1.34	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 140 kb · p 5.3e-20 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P544R vs ClinVar P545R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,126 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,162 alleles · very rare exomes 2/1,460,854 · genomes 0/152,308 · 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: PHF21A
Protein: p.Pro545Arg
Coding: c.1634C>G
MANE Select: NM_001352027
Type: single nucleotide variant
Location: chr11:45936544 (GRCh38)
Gene constraint: LOEUF 0.149 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.12 · 2 PDB
Residue 544 UniProt numbering: the 'required for transcriptional repression' region

Full PHF21A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHF21A p.Arg59Trp Uncertain significance ★★ ⚠ same condition
PHF21A p.Asn655Asp Uncertain significance ★★ ⚠ same condition
PHF21A p.Asp630Asn Uncertain significance ★★ ⚠ same condition
PHF21A p.His104Tyr Uncertain significance ★★ ⚠ same condition
PHF21A p.His423Pro Uncertain significance ★★ ⚠ same condition
PHF21A p.Ile162Val Uncertain significance ★★ ⚠ same condition
PHF21A p.Lys238Arg Uncertain significance ★★ ⚠ same condition
PHF21A p.Met599Val Uncertain significance ★★ ⚠ same condition

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/phf21a-p-pro545arg (accessed [today's date]).

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