Is PHF8 p.Asp73Glu (c.219T>A) pathogenic?

PHF8 p.Asp73Glu (c.219T>A) is classified Benign/Likely benign in PHF8 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-09). AlphaMissense: likely benign (0.1056); Low-frequency (popmax 1.94%, mid); Associated with Inborn genetic diseases.

What condition is associated with PHF8 p.Asp73Glu (c.219T>A)?

PHF8 p.Asp73Glu (c.219T>A) is associated with Inborn genetic diseases (ClinVar).

How common is PHF8 p.Asp73Glu (c.219T>A) in the general population?

PHF8 p.Asp73Glu (c.219T>A) is low-frequency (popmax 1.94%, mid) (gnomAD).

What do computational predictors say about PHF8 p.Asp73Glu (c.219T>A)?

AlphaMissense predicts likely benign (score 0.1056) — an in-silico prediction, not a clinical call.

PHF8 p.Asp73Glu

c.219T>A · rs148664730 · VCV516469

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1056 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.94%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1056	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -5.88	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 1.7	phastCons 0.059
Regional constraint	o/e 0.84	unconstrained · MANE · 4,540 bp · p 0.35 · regional, not allelic
Overall
CADD	11.63	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 D109E vs ClinVar D73E) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.94% Middle Eastern · 84/4,340 alleles

Filtering AF 1.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.48%

Overall 0.166% 2,001/1,204,307 alleles · low-frequency exomes 1,844/1,092,517 · genomes 157/111,790 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.94%	52
South Asian	0.64%	156
Ashkenazi Jewishnot grpmax-eligible	0.291%	343
Remaining individualsnot grpmax-eligible	0.205%	489
Admixed American	0.204%	491
European (non-Finnish)	0.143%	698
African / African-American	0.0385%	2,597
Finnishnot grpmax-eligible	0.00429%	23,309

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: PHF8
Protein: p.Asp73Glu
Coding: c.219T>A
MANE Select: NM_015107
dbSNP: rs148664730
Type: single nucleotide variant
Location: chrX:54022333 (GRCh38)
Structure: AlphaFold pLDDT 63.30 · 6 PDB
Residue 109 UniProt numbering: the 'disordered' region; the 'linker' region

Full PHF8 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

PHF8 p.Asp73Gly Uncertain significance ★ ⚠ same residue
PHF8 p.Arg506Ter Pathogenic/Likely pathogenic ★★ same condition
PHF8 p.Ala770Pro Uncertain significance ★★ ⚠ same condition
PHF8 p.Arg240Gln Uncertain significance ★★ ⚠ same condition
PHF8 p.Arg438His Uncertain significance ★★ same condition
PHF8 p.Arg588Gln Uncertain significance ★★ ⚠ same condition
PHF8 p.Arg773Pro Uncertain significance ★★ ⚠ same condition
PHF8 p.Arg968Cys 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/phf8-p-asp73glu (accessed [today's date]).

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