Is ANKIB1 p.Pro49Ser (c.145C>T) pathogenic?

ANKIB1 p.Pro49Ser (c.145C>T) is classified Uncertain significance in ANKIB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely pathogenic (0.8074); Very rare (popmax 0.000259%, nfe).

How common is ANKIB1 p.Pro49Ser (c.145C>T) in the general population?

ANKIB1 p.Pro49Ser (c.145C>T) is very rare (popmax 0.000259%, nfe) (gnomAD).

What do computational predictors say about ANKIB1 p.Pro49Ser (c.145C>T)?

AlphaMissense predicts likely pathogenic (score 0.8074) — an in-silico prediction, not a clinical call.

ANKIB1 p.Pro49Ser

c.145C>T · VCV4052969

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8074 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000259%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8074	likely pathogenic
REVEL	0.68	pathogenic-leaning
SaProt	LLR -7.96	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 4.1, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 12 kb · p 3.8e-08 · regional, not allelic
Overall
CADD	27.1	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 0.000259% European (non-Finnish) · 3/1,156,198 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000191% 3/1,569,410 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: ANKIB1
Protein: p.Pro49Ser
Coding: c.145C>T
MANE Select: NM_019004
Type: single nucleotide variant
Location: chr7:92295123 (GRCh38)
Gene constraint: LOEUF 0.533 · pLI 0.34 (gnomAD)
Structure: AlphaFold pLDDT 66.52

Full ANKIB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKIB1 c.-605T>C Benign/Likely benign ★★ same type
ANKIB1 p.Ala1062Val Uncertain significance ★ ⚠ same type
ANKIB1 p.Ala126Thr Uncertain significance ★ ⚠ same type
ANKIB1 p.Ala218Thr Uncertain significance ★ ⚠ same type
ANKIB1 p.Ala257Gly Uncertain significance ★ ⚠ same type
ANKIB1 p.Ala986Val Uncertain significance ★ ⚠ same type
ANKIB1 p.Arg102Cys Uncertain significance ★ same type
ANKIB1 p.Arg102Leu 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/ankib1-p-pro49ser (accessed [today's date]).

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