Is ST14 p.Pro740Arg (c.2219C>G) pathogenic?

ST14 p.Pro740Arg (c.2219C>G) is classified Uncertain significance in ST14 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-22). AlphaMissense: likely benign (0.1323); Ultra-rare (popmax 0.015%, amr); Associated with Inborn genetic diseases.

What condition is associated with ST14 p.Pro740Arg (c.2219C>G)?

ST14 p.Pro740Arg (c.2219C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ST14 p.Pro740Arg (c.2219C>G) in the general population?

ST14 p.Pro740Arg (c.2219C>G) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about ST14 p.Pro740Arg (c.2219C>G)?

AlphaMissense predicts likely benign (score 0.1323) — an in-silico prediction, not a clinical call.

ST14 p.Pro740Arg

c.2219C>G · rs757752489 · VCV2345408

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1323 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1323	likely benign
REVEL	0.682	pathogenic-leaning
SaProt	LLR -8.08	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 50 kb · p 0.00036 · regional, not allelic
Overall
CADD	24.2	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 0.015% Admixed American · 9/60,002 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.000991% 16/1,613,920 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,667
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Remaining individualsnot grpmax-eligible	0.0032%	31,233
European (non-Finnish)	0.000339%	295,002

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: ST14
Protein: p.Pro740Arg
Coding: c.2219C>G
MANE Select: NM_021978
dbSNP: rs757752489
Type: single nucleotide variant
Location: chr11:130208634 (GRCh38)
Gene constraint: LOEUF 0.589 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.23 · 25 PDB
Residue 740: the peptidase s1 domain

Full ST14 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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ST14 p.Gly272Ser Uncertain significance ★★ ⚠ same condition
ST14 p.Gly642Ser Uncertain significance ★★ ⚠ same condition
ST14 p.Lys743Asn Uncertain significance ★★ ⚠ same condition
ST14 p.Pro526Leu Uncertain significance ★★ ⚠ same condition
ST14 p.Ser449Phe Uncertain significance ★★ ⚠ same condition
ST14 p.Thr419Ala Uncertain significance ★★ ⚠ same condition

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/st14-p-pro740arg (accessed [today's date]).

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