Is PHF8 p.Val448Ala (c.1343T>C) pathogenic?

PHF8 p.Val448Ala (c.1343T>C) is classified Uncertain significance in PHF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-03-02). AlphaMissense: likely benign (0.1925); Very rare (popmax 0.00218%, amr).

How common is PHF8 p.Val448Ala (c.1343T>C) in the general population?

PHF8 p.Val448Ala (c.1343T>C) is very rare (popmax 0.00218%, amr) (gnomAD).

What do computational predictors say about PHF8 p.Val448Ala (c.1343T>C)?

AlphaMissense predicts likely benign (score 0.1925) — an in-silico prediction, not a clinical call.

PHF8 p.Val448Ala

c.1343T>C · rs1064796692 · VCV423906

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00218%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1925	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -4.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 12 kb · p 0.36 · regional, not allelic
Overall
CADD	21.5	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM V484A vs ClinVar V448A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00218% Admixed American · 1/45,873 alleles

Overall 8.3e-05% 1/1,204,236 alleles · very rare exomes 1/1,090,564 · genomes 0/113,672 · 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: PHF8
Protein: p.Val448Ala
Coding: c.1343T>C
MANE Select: NM_015107
dbSNP: rs1064796692
Type: single nucleotide variant
Location: chrX:53993884 (GRCh38)
Structure: AlphaFold pLDDT 63.30 · 6 PDB

Full PHF8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PHF8 p.Arg240Ter Likely pathogenic ★★ same type
PHF8 p.Arg506Ter Pathogenic/Likely pathogenic ★★ same type
PHF8 p.Arg753Ter Pathogenic/Likely pathogenic ★★ same type
PHF8 p.Gln539Ter Pathogenic ★★ same type
PHF8 p.Ser737Ter Pathogenic/Likely pathogenic ★★ same type
PHF8 p.Ala770Pro Uncertain significance ★★ ⚠ same type
PHF8 p.Ala888Ser Uncertain significance ★★ ⚠ same type
PHF8 p.Arg240Gln 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/phf8-p-val448ala (accessed [today's date]).

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