Is PHC1 p.Val459Phe (c.1375G>T) pathogenic?

PHC1 p.Val459Phe (c.1375G>T) is classified Uncertain significance in PHC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-12). AlphaMissense: likely benign (0.1353); Ultra-rare (popmax 0.0734%, mid).

How common is PHC1 p.Val459Phe (c.1375G>T) in the general population?

PHC1 p.Val459Phe (c.1375G>T) is ultra-rare (popmax 0.0734%, mid) (gnomAD).

What do computational predictors say about PHC1 p.Val459Phe (c.1375G>T)?

AlphaMissense predicts likely benign (score 0.1353) — an in-silico prediction, not a clinical call.

PHC1 p.Val459Phe

c.1375G>T · rs754554396 · VCV2356804

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1353 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0734%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1353	likely benign
REVEL	0.074	moderately benign-leaning
SaProt	LLR -9.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.48	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.20	constrained · MANE · 446 bp · p 5e-20 · regional, not allelic
Overall
CADD	25.7	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 0.0734% Middle Eastern · 4/5,450 alleles

Filtering AF 0.029% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0247%

Overall 0.0137% 187/1,360,406 alleles · ultra-rare exomes 165/1,210,946 · genomes 22/149,460 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0734%	1,362
Admixed American	0.0421%	2,375
Remaining individualsnot grpmax-eligible	0.0369%	2,710
European (non-Finnish)	0.0139%	7,170
African / African-American	0.00723%	13,822
South Asian	0.00116%	85,872

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: PHC1
Protein: p.Val459Phe
Coding: c.1375G>T
MANE Select: NM_004426
dbSNP: rs754554396
Type: single nucleotide variant
Location: chr12:8932832 (GRCh38)
Gene constraint: LOEUF 0.322 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 51.06 · 1 PDB
Residue 459: the 'disordered' region

Full PHC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PHC1 p.Arg876Gln Uncertain significance ★★ ⚠ same type
PHC1 p.Arg876Trp Uncertain significance ★★ ⚠ same type
PHC1 p.Arg939His Uncertain significance ★★ ⚠ same type
PHC1 p.Glu684Ala Uncertain significance ★★ ⚠ same type
PHC1 p.His629Asn Uncertain significance ★★ ⚠ same type
PHC1 c.1106-60G>A Benign ★★ same type
PHC1 c.114+191T>C Benign ★★ same type
PHC1 c.1894-221A>G Benign ★★ 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/phc1-p-val459phe (accessed [today's date]).

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