Is ANKRD53 p.Pro392Ser (c.1174C>T) pathogenic?

ANKRD53 p.Pro392Ser (c.1174C>T) is classified Uncertain significance in ANKRD53 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-23). AlphaMissense: likely benign (0.2522); Ultra-rare (popmax 0.0535%, sas).

How common is ANKRD53 p.Pro392Ser (c.1174C>T) in the general population?

ANKRD53 p.Pro392Ser (c.1174C>T) is ultra-rare (popmax 0.0535%, sas) (gnomAD).

What do computational predictors say about ANKRD53 p.Pro392Ser (c.1174C>T)?

AlphaMissense predicts likely benign (score 0.2522) — an in-silico prediction, not a clinical call.

ANKRD53 p.Pro392Ser

c.1174C>T · VCV4108284

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2522 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0535%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2522	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -6.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.7	GERP 1.7, phastCons 0.009
Regional constraint	o/e 0.95	unconstrained · MANE · 6,651 bp · p 0.15 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0535% South Asian · 45/84,068 alleles

Filtering AF 0.0411% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0367%

Overall 0.00297% 46/1,550,994 alleles · ultra-rare exomes 45/1,398,792 · genomes 1/152,202 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0535%	1,868
Remaining individualsnot grpmax-eligible	0.00166%	60,086

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: ANKRD53
Protein: p.Pro392Ser
Coding: c.1174C>T
MANE Select: NM_001115116
Type: single nucleotide variant
Location: chr2:70984881 (GRCh38)
Gene constraint: LOEUF 1.379 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.41
Residue 392: the 'disordered' region

Full ANKRD53 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKRD53 p.Ala11Glu Uncertain significance ★ ⚠ same type
ANKRD53 p.Ala143Asp Uncertain significance ★ ⚠ same type
ANKRD53 p.Ala148Thr Uncertain significance ★ same type
ANKRD53 p.Ala219Ser Uncertain significance ★ ⚠ same type
ANKRD53 p.Ala242Thr Uncertain significance ★ ⚠ same type
ANKRD53 p.Ala310Thr Uncertain significance ★ ⚠ same type
ANKRD53 p.Ala39Pro Uncertain significance ★ ⚠ same type
ANKRD53 p.Ala434Pro 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/ankrd53-p-pro392ser (accessed [today's date]).

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