Is PHC1 p.Pro123= (c.369C>T) pathogenic?

PHC1 p.Pro123= (c.369C>T) is classified Benign in PHC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-09-05). Common (popmax 83.1%, sas) — too common for a highly-penetrant pathogenic allele; Associated with microcephaly 11, primary, autosomal recessive.

What condition is associated with PHC1 p.Pro123= (c.369C>T)?

PHC1 p.Pro123= (c.369C>T) is associated with microcephaly 11, primary, autosomal recessive (ClinVar).

PHC1 p.Pro123=

Q: How common is PHC1 p.Pro123= (c.369C>T) in the general population?

PHC1 p.Pro123= (c.369C>T) is common (popmax 83.1%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.369C>T · rs1805741 · VCV1252581

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 83.1%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

microcephaly 11, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.63	GERP -2.2, phastCons 1
Overall
CADD	11.43	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 83.1% South Asian · 75,561/90,978 alleles

Filtering AF 82.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 82.4%

Overall 70.2% 1,131,599/1,612,636 alleles · common exomes 1,036,883/1,460,718 · genomes 94,716/151,918 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	83.1%	1
Ashkenazi Jewishnot grpmax-eligible	79.8%	1
Middle Eastern	76.4%	1
East Asian	72.7%	1
European (non-Finnish)	71.2%	1
Remaining individualsnot grpmax-eligible	70.8%	1
Finnishnot grpmax-eligible	66%	2
Amishnot grpmax-eligible	63.5%	2
Admixed American	61.5%	2
African / African-American	42.8%	2

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.Pro123=
Coding: c.369C>T
MANE Select: NM_004426
dbSNP: rs1805741
Type: single nucleotide variant
Location: chr12:8921663 (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.Pro123Leu Uncertain significance ★ ⚠ same residue
PHC1 p.Pro123Ser 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.Thr693Ala Benign ★★ same condition
PHC1 p.Arg34Ter Pathogenic ★ 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-pro123 (accessed [today's date]).

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