Is PHC1 p.Arg34Gln (c.101G>A) pathogenic?

PHC1 p.Arg34Gln (c.101G>A) is classified Uncertain significance in PHC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-18). AlphaMissense: likely pathogenic (0.8441); Very rare (popmax 0.00278%, afr).

How common is PHC1 p.Arg34Gln (c.101G>A) in the general population?

PHC1 p.Arg34Gln (c.101G>A) is very rare (popmax 0.00278%, afr) (gnomAD).

What do computational predictors say about PHC1 p.Arg34Gln (c.101G>A)?

AlphaMissense predicts likely pathogenic (score 0.8441) — an in-silico prediction, not a clinical call.

PHC1 p.Arg34Gln

c.101G>A · rs377364177 · VCV1336643

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8441 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00278%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8441	likely pathogenic
REVEL	0.232	benign-leaning
SaProt	LLR -4.87	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 13 kb · p 2.3e-07 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00278% African / African-American · 2/72,056 alleles

Filtering AF 0.000635% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000489%

Overall 0.00109% 17/1,556,136 alleles · very rare exomes 15/1,403,996 · genomes 2/152,140 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00278%	36,028
East Asian	0.00242%	41,360
Finnishnot grpmax-eligible	0.00157%	63,764
European (non-Finnish)	0.00114%	87,848

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.Arg34Gln
Coding: c.101G>A
MANE Select: NM_004426
dbSNP: rs377364177
Type: single nucleotide variant
Location: chr12:8917778 (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

Similar variants

PHC1 p.Arg34Ter Pathogenic ★ same residue
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

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-arg34gln (accessed [today's date]).

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