Is ANKRD54 p.Pro212Ala (c.634C>G) pathogenic?

ANKRD54 p.Pro212Ala (c.634C>G) is classified Uncertain significance in ANKRD54 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-29). AlphaMissense: likely pathogenic (0.7293); Very rare (popmax 0.000169%, nfe).

How common is ANKRD54 p.Pro212Ala (c.634C>G) in the general population?

ANKRD54 p.Pro212Ala (c.634C>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ANKRD54 p.Pro212Ala (c.634C>G)?

AlphaMissense predicts likely pathogenic (score 0.7293) — an in-silico prediction, not a clinical call.

ANKRD54 p.Pro212Ala

c.634C>G · VCV3399085

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7293 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7293	likely pathogenic
REVEL	0.593	indeterminate
SaProt	LLR -7.63	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 6,644 bp · p 0.0026 · regional, not allelic
Overall
CADD	24.9	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 0.000169% European (non-Finnish) · 2/1,179,998 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,854 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)grpmax	0.000169%	589,998

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ANKRD54
Protein: p.Pro212Ala
Coding: c.634C>G
MANE Select: NM_138797
Type: single nucleotide variant
Location: chr22:37833044 (GRCh38)
Gene constraint: LOEUF 1.126 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.74
Residue 212: the 'lyn-binding' region

Full ANKRD54 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKRD54 p.Pro212Thr Uncertain significance ★ ⚠ same residue
ANKRD54 p.Leu163= Benign ★★ same type
ANKRD54 p.Ala134Thr Uncertain significance ★ ⚠ same type
ANKRD54 p.Ala233Val Uncertain significance ★ ⚠ same type
ANKRD54 p.Ala40Thr Uncertain significance ★ ⚠ same type
ANKRD54 p.Ala88Thr Uncertain significance ★ ⚠ same type
ANKRD54 p.Arg144Cys Uncertain significance ★ ⚠ same type
ANKRD54 p.Arg172Gln 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/ankrd54-p-pro212ala (accessed [today's date]).

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