Is PHF20 p.Pro249Ser (c.745C>T) pathogenic?

PHF20 p.Pro249Ser (c.745C>T) is classified Uncertain significance in PHF20 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-11). AlphaMissense: likely benign (0.0843); Very rare (popmax 0.00017%, nfe).

How common is PHF20 p.Pro249Ser (c.745C>T) in the general population?

PHF20 p.Pro249Ser (c.745C>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about PHF20 p.Pro249Ser (c.745C>T)?

AlphaMissense predicts likely benign (score 0.0843) — an in-silico prediction, not a clinical call.

PHF20 p.Pro249Ser

c.745C>T · rs2515995461 · VCV3212126

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0843 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0843	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -5.28	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 3.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 116 kb · p 3.5e-12 · regional, not allelic
Overall
CADD	21.2	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 0.00017% European (non-Finnish) · 2/1,179,576 alleles

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

Overall 0.000124% 2/1,612,276 alleles · very rare exomes 2/1,460,006 · genomes 0/152,270 · 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: PHF20
Protein: p.Pro249Ser
Coding: c.745C>T
MANE Select: NM_016436
dbSNP: rs2515995461
Type: single nucleotide variant
Location: chr20:35863337 (GRCh38)
Gene constraint: LOEUF 0.249 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 55.32 · 7 PDB
Residue 249: the 'disordered' region

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-pro249ser (accessed [today's date]).

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