Is C4A p.Pro1122Ser (c.3364C>T) pathogenic?

C4A p.Pro1122Ser (c.3364C>T) is classified Uncertain significance in C4A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely benign (0.3333); Very rare (popmax 0.00406%, nfe); Associated with Inborn genetic diseases.

What condition is associated with C4A p.Pro1122Ser (c.3364C>T)?

C4A p.Pro1122Ser (c.3364C>T) is associated with Inborn genetic diseases (ClinVar).

How common is C4A p.Pro1122Ser (c.3364C>T) in the general population?

C4A p.Pro1122Ser (c.3364C>T) is very rare (popmax 0.00406%, nfe) (gnomAD).

What do computational predictors say about C4A p.Pro1122Ser (c.3364C>T)?

AlphaMissense predicts likely benign (score 0.3333) — an in-silico prediction, not a clinical call.

C4A p.Pro1122Ser

c.3364C>T · rs770277641 · VCV2475100

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3333 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00406%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3333	likely benign
REVEL	0.195	benign-leaning
SaProt	LLR -7.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Overall
CADD	20.8	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 0.00406% European (non-Finnish) · 47/1,156,716 alleles

Filtering AF 0.00313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00281%

Overall 0.00296% 47/1,587,548 alleles · very rare exomes 46/1,437,974 · genomes 1/149,574 · 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: C4A
Protein: p.Pro1122Ser
Coding: c.3364C>T
MANE Select: NM_007293
dbSNP: rs770277641
Type: single nucleotide variant
Location: chr6:31996088 (GRCh38)
Gene constraint: LOEUF 0.752 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 83.56 · 12 PDB

Full C4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C4A p.Ala1062Val Uncertain significance ★ ⚠ same condition
C4A p.Ala1080Gly Uncertain significance ★ ⚠ same condition
C4A p.Ala1148Val Uncertain significance ★ ⚠ same condition
C4A p.Ala1190Ser Uncertain significance ★ ⚠ same condition
C4A p.Ala1199Thr Uncertain significance ★ ⚠ same condition
C4A p.Ala1205Val Uncertain significance ★ ⚠ same condition
C4A p.Ala1259Thr Uncertain significance ★ ⚠ same condition
C4A p.Ala891Val 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/c4a-p-pro1122ser (accessed [today's date]).

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