Is PHF6 p.His43Pro (c.128A>C) pathogenic?

PHF6 p.His43Pro (c.128A>C) is classified Uncertain significance in PHF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-01). AlphaMissense: likely pathogenic (0.8594); Absent from gnomAD v4.1.

How common is PHF6 p.His43Pro (c.128A>C) in the general population?

PHF6 p.His43Pro (c.128A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHF6 p.His43Pro (c.128A>C)?

AlphaMissense predicts likely pathogenic (score 0.8594) — an in-silico prediction, not a clinical call.

PHF6 p.His43Pro

c.128A>C · rs1273843884 · VCV3027008

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8594 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8594	likely pathogenic
REVEL	0.66	pathogenic-leaning
SaProt	LLR -9.09	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 36 kb · p 6.2e-06 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

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: PHF6
Protein: p.His43Pro
Coding: c.128A>C
MANE Select: NM_001015877
dbSNP: rs1273843884
Type: single nucleotide variant
Location: chrX:134377745 (GRCh38)
Structure: AlphaFold pLDDT 73.45 · 2 PDB
Residue 43: the 'extended phd1 domain (ephd1)' region

Full PHF6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PHF6 p.His43Arg Uncertain significance ★★ same residue
PHF6 p.Arg116Ter Pathogenic ★★ same type
PHF6 p.Arg225Ter Pathogenic ★★ same type
PHF6 p.Arg274Ter Pathogenic ★★ same type
PHF6 p.Arg342Ter Pathogenic ★★ same type
PHF6 p.Cys45Tyr Pathogenic ★★ same type
PHF6 p.Met1Thr Pathogenic ★★ same type
PHF6 p.Arg163His 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/phf6-p-his43pro (accessed [today's date]).

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