Is C7 p.Leu421Pro (c.1262T>C) pathogenic?

C7 p.Leu421Pro (c.1262T>C) is classified Uncertain significance in C7 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-05). AlphaMissense: ambiguous (0.4015); Very rare (popmax 0.0011%, sas).

How common is C7 p.Leu421Pro (c.1262T>C) in the general population?

C7 p.Leu421Pro (c.1262T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about C7 p.Leu421Pro (c.1262T>C)?

AlphaMissense predicts ambiguous (score 0.4015) — an in-silico prediction, not a clinical call.

C7 p.Leu421Pro

c.1262T>C · rs1156578432 · VCV1351472

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4015 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4015	ambiguous
REVEL	0.87	moderately pathogenic-leaning
SaProt	LLR -11.54	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.67 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5	GERP 2.1, phastCons 1
Overall
CADD	25.1	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 0.0011% South Asian · 1/90,584 alleles

Overall 6.86e-05% 1/1,456,916 alleles · very rare

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: C7
Protein: p.Leu421Pro
Coding: c.1262T>C
MANE Select: NM_001565 · reported on NM_000587
dbSNP: rs1156578432
Type: single nucleotide variant
Location: chr5:40958034 (GRCh38)
Structure: AlphaFold pLDDT 89.67 · 6 PDB

Full C7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C7 c.281-1G>T Pathogenic/Likely pathogenic ★★ same type
C7 c.63-1G>A Pathogenic ★★ same type
C7 c.739-2A>G Likely pathogenic ★★ same type
C7 p.Arg402Ter Pathogenic/Likely pathogenic ★★ same type
C7 p.Gln271Ter Pathogenic/Likely pathogenic ★★ same type
C7 p.Gly379Arg Pathogenic/Likely pathogenic ★★ ⚠ same type
C7 p.Trp205Ter Pathogenic/Likely pathogenic ★★ same type
C7 p.Ala359Thr 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/c7-p-leu421pro (accessed [today's date]).

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