Is ANG p.Pro136Leu (c.407C>T) pathogenic?

ANG p.Pro136Leu (c.407C>T) is classified Conflicting classifications of pathogenicity in ANG (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-30). AlphaMissense: likely pathogenic (0.6786); Very rare (popmax 0.00833%, amr); Associated with ANG-related disorder.

What condition is associated with ANG p.Pro136Leu (c.407C>T)?

ANG p.Pro136Leu (c.407C>T) is associated with ANG-related disorder, amyotrophic lateral sclerosis type 9 (ClinVar).

How common is ANG p.Pro136Leu (c.407C>T) in the general population?

ANG p.Pro136Leu (c.407C>T) is very rare (popmax 0.00833%, amr) (gnomAD).

What do computational predictors say about ANG p.Pro136Leu (c.407C>T)?

AlphaMissense predicts likely pathogenic (score 0.6786) — an in-silico prediction, not a clinical call.

ANG p.Pro136Leu

c.407C>T · rs121909543 · VCV18081

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6786 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ANG-related disorder

Computational evidence

Protein change
AlphaMissense	0.6786	likely pathogenic
REVEL	0.734	pathogenic-leaning
SaProt	LLR -10.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 0.58, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 440 bp · p 0.49 · regional, not allelic
Overall
CADD	22.8	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 0.00833% Admixed American · 5/59,990 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00167% 27/1,613,982 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	11,998
European (non-Finnish)	0.00186%	53,638

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: ANG
Protein: p.Pro136Leu
Coding: c.407C>T
MANE Select: NM_001097577
dbSNP: rs121909543
Type: single nucleotide variant
Location: chr14:20693971 (GRCh38)
Gene constraint: LOEUF 1.697 · pLI 0.42 (gnomAD)
Structure: AlphaFold pLDDT 90.50 · 56 PDB
Residue 136: a UniProt-annotated variant site (in als9; loss of angiogenic activity; reduced trna ribonucleolytic activity; unable to translocate to the nucleus); a β-strand

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

Disease context

ANG-related disorder

Also linked: amyotrophic lateral sclerosis type 9

Similar variants

ANG p.Arg75His Uncertain significance ★★ ⚠ same condition
ANG p.Pro21Leu Uncertain significance ★★ ⚠ same condition
ANG c.-237A>C Benign ★★ same condition
ANG c.-332C>A Benign ★★ same condition
ANG c.-401G>T Benign ★★ same condition
ANG c.-41T>C Benign ★★ same condition
ANG c.-530T>C Benign ★★ same condition
ANG c.-534C>T Benign ★★ 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/ang-p-pro136leu (accessed [today's date]).

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