Is PHC1 p.Arg34Ter (c.100C>T) pathogenic?

PHC1 p.Arg34Ter (c.100C>T) is classified Pathogenic in PHC1 (ClinVar, Single submitter, 1 submitter). Very rare (popmax 0.000175%, nfe); Associated with microcephaly 11, primary, autosomal recessive.

What condition is associated with PHC1 p.Arg34Ter (c.100C>T)?

PHC1 p.Arg34Ter (c.100C>T) is associated with microcephaly 11, primary, autosomal recessive (ClinVar).

How common is PHC1 p.Arg34Ter (c.100C>T) in the general population?

PHC1 p.Arg34Ter (c.100C>T) is very rare (popmax 0.000175%, nfe) (gnomAD).

PHC1 p.Arg34Ter

c.100C>T · rs2137054010 · VCV1332797

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000175%, nfe)

Conditions

microcephaly 11, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 2 of 15
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Overall
CADD	41.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000175% European (non-Finnish) · 2/1,144,192 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000128% 2/1,558,518 alleles · very rare exomes 2/1,406,276 · genomes 0/152,242 · 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: PHC1
Protein: p.Arg34Ter
Coding: c.100C>T
MANE Select: NM_004426
dbSNP: rs2137054010
Type: single nucleotide variant
Location: chr12:8917777 (GRCh38)
Gene constraint: LOEUF 0.322 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 51.06 · 1 PDB

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

Disease context

microcephaly 11, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHC1 p.Arg34Gln Uncertain significance ★ ⚠ same residue
PHC1 p.Arg876Trp Uncertain significance ★★ ⚠ same condition
PHC1 c.2860+12C>T Benign ★★ same condition
PHC1 p.Arg306= Benign ★★ same condition
PHC1 p.Leu31= Benign ★★ same condition
PHC1 p.Pro123= Benign ★★ same condition
PHC1 p.Thr693Ala Benign ★★ same condition
PHC1 p.Met593Leu 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/phc1-p-arg34ter (accessed [today's date]).

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