Is ANKRD31 p.Phe1453Cys (c.4358T>G) pathogenic?

ANKRD31 p.Phe1453Cys (c.4358T>G) is classified Uncertain significance in ANKRD31 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-07). AlphaMissense: likely pathogenic (0.8051); Ultra-rare (popmax 0.0318%, eas).

How common is ANKRD31 p.Phe1453Cys (c.4358T>G) in the general population?

ANKRD31 p.Phe1453Cys (c.4358T>G) is ultra-rare (popmax 0.0318%, eas) (gnomAD).

What do computational predictors say about ANKRD31 p.Phe1453Cys (c.4358T>G)?

AlphaMissense predicts likely pathogenic (score 0.8051) — an in-silico prediction, not a clinical call.

ANKRD31 p.Phe1453Cys

c.4358T>G · VCV3297375

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8051 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0318%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8051	likely pathogenic · top 2% in ANKRD31
REVEL	0.482	indeterminate
SaProt	LLR -7.69	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 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 168 kb · p 0.00044 · 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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F1396C vs ClinVar F1453C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0318% East Asian · 13/40,876 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0149%

Overall 0.000917% 14/1,526,228 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0318%	3,144
European (non-Finnish)	8.75e-05%	1,143,362

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: ANKRD31
Protein: p.Phe1453Cys
Coding: c.4358T>G
MANE Select: NM_001372053
Type: single nucleotide variant
Location: chr5:75105201 (GRCh38)
Gene constraint: LOEUF 0.844 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 43.08
Residue 1453: the 'disordered' region

Full ANKRD31 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ANKRD31 p.Arg1353Gln Benign ★★ same type
ANKRD31 p.Asn192Ile Benign ★★ same type
ANKRD31 c.1565-2A>G Pathogenic ★ same type
ANKRD31 p.Gln329Ter Pathogenic ★ same type
ANKRD31 p.Ala1011Asp Uncertain significance ★ ⚠ same type
ANKRD31 p.Ala1021Thr Uncertain significance ★ ⚠ same type
ANKRD31 p.Ala1294Thr Uncertain significance ★ ⚠ same type
ANKRD31 p.Ala1302Thr 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/ankrd31-p-phe1453cys (accessed [today's date]).

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