Is ANLN p.Pro43Ser (c.127C>T) pathogenic?

ANLN p.Pro43Ser (c.127C>T) is classified Uncertain significance in ANLN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-10). AlphaMissense: ambiguous (0.4612); Very rare (popmax 0.00675%, nfe).

How common is ANLN p.Pro43Ser (c.127C>T) in the general population?

ANLN p.Pro43Ser (c.127C>T) is very rare (popmax 0.00675%, nfe) (gnomAD).

What do computational predictors say about ANLN p.Pro43Ser (c.127C>T)?

AlphaMissense predicts ambiguous (score 0.4612) — an in-silico prediction, not a clinical call.

ANLN p.Pro43Ser

c.127C>T · rs745699628 · VCV2429491

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4612 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00675%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4612	ambiguous
REVEL	0.437	indeterminate
SaProt	LLR -7.82	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 37 kb · p 0.00088 · regional, not allelic
Overall
CADD	25.2	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 0.00675% European (non-Finnish) · 79/1,169,888 alleles

Filtering AF 0.00551% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0051%

Overall 0.00506% 81/1,600,740 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00675%	14,809
Remaining individualsnot grpmax-eligible	0.00162%	61,756
African / African-American	0.00134%	74,716

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: ANLN
Protein: p.Pro43Ser
Coding: c.127C>T
MANE Select: NM_018685
dbSNP: rs745699628
Type: single nucleotide variant
Location: chr7:36396374 (GRCh38)
Gene constraint: LOEUF 0.537 · pLI 0.08 (gnomAD)
Structure: AlphaFold pLDDT 60.09 · 3 PDB
Residue 43: the 'nuclear localization' region; the 'interaction with cd2ap' region; the 'disordered' region; the 'required for ubiquitination' region

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

Similar variants

ANLN p.Pro43Leu Likely benign ★ same residue
ANLN p.Arg431Cys Pathogenic/Likely pathogenic ★★ same type
ANLN c.2653-13G>A Uncertain significance ★★ same type
ANLN p.Ala47Gly Uncertain significance ★★ ⚠ same type
ANLN p.Ala828Thr Uncertain significance ★★ ⚠ same type
ANLN p.Ala940Thr Uncertain significance ★★ ⚠ same type
ANLN p.Arg1040His Uncertain significance ★★ ⚠ same type
ANLN p.Arg154Cys 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/anln-p-pro43ser (accessed [today's date]).

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