Is C2CD4C p.Pro54His (c.161C>A) pathogenic?

C2CD4C p.Pro54His (c.161C>A) is classified Uncertain significance in C2CD4C (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: likely pathogenic (0.9203); Very rare (popmax 0.00774%, eas).

How common is C2CD4C p.Pro54His (c.161C>A) in the general population?

C2CD4C p.Pro54His (c.161C>A) is very rare (popmax 0.00774%, eas) (gnomAD).

What do computational predictors say about C2CD4C p.Pro54His (c.161C>A)?

AlphaMissense predicts likely pathogenic (score 0.9203) — an in-silico prediction, not a clinical call.

C2CD4C p.Pro54His

c.161C>A · rs757325726 · VCV2235299

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9203 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00774%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9203	likely pathogenic · top 8% in C2CD4C
REVEL	0.672	pathogenic-leaning
SaProt	LLR -9.30	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 1,262 bp · p 0.088 · regional, not allelic
Overall
CADD	28.6	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 0.00774% East Asian · 3/38,754 alleles

Filtering AF 0.00205% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00107%

Overall 0.0011% 16/1,460,752 alleles · very rare exomes 14/1,308,642 · genomes 2/152,110 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00774%	12,918
African / African-American	0.00146%	68,394
European (non-Finnish)	0.00108%	92,225

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: C2CD4C
Protein: p.Pro54His
Coding: c.161C>A
MANE Select: NM_001136263
dbSNP: rs757325726
Type: single nucleotide variant
Location: chr19:408201 (GRCh38)
Gene constraint: LOEUF 1.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.88
Residue 54: the 'disordered' region

Full C2CD4C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C2CD4C p.Pro54Arg Uncertain significance ★ ⚠ same residue
C2CD4C p.Pro54Ser Uncertain significance ★ ⚠ same residue
C2CD4C p.Ala107Thr Uncertain significance ★ ⚠ same type
C2CD4C p.Ala151Ser Uncertain significance ★ ⚠ same type
C2CD4C p.Ala154Ser Uncertain significance ★ ⚠ same type
C2CD4C p.Ala181Pro Uncertain significance ★ ⚠ same type
C2CD4C p.Ala187Val Uncertain significance ★ ⚠ same type
C2CD4C p.Ala203Val 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/c2cd4c-p-pro54his (accessed [today's date]).

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