Is ALKAL2 p.Pro78Ser (c.232C>T) pathogenic?

ALKAL2 p.Pro78Ser (c.232C>T) is classified Uncertain significance in ALKAL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-13). AlphaMissense: likely benign (0.0764); Ultra-rare (popmax 0.0118%, afr).

How common is ALKAL2 p.Pro78Ser (c.232C>T) in the general population?

ALKAL2 p.Pro78Ser (c.232C>T) is ultra-rare (popmax 0.0118%, afr) (gnomAD).

What do computational predictors say about ALKAL2 p.Pro78Ser (c.232C>T)?

AlphaMissense predicts likely benign (score 0.0764) — an in-silico prediction, not a clinical call.

ALKAL2 p.Pro78Ser

c.232C>T · VCV4041336

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0764 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0118%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0764	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -6.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -2.5, phastCons 0.33
Regional constraint	o/e 1.14	unconstrained · MANE · 7,685 bp · p 0.04 · regional, not allelic
Overall
CADD	8.056	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 0.0118% African / African-American · 8/67,946 alleles

Filtering AF 0.00585% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00424%

Overall 0.000748% 11/1,469,646 alleles · ultra-rare exomes 3/1,317,490 · genomes 8/152,156 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0118%	8,493
South Asian	0.00131%	76,584
European (non-Finnish)	0.000179%	558,338

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: ALKAL2
Protein: p.Pro78Ser
Coding: c.232C>T
MANE Select: NM_001002919
Type: single nucleotide variant
Location: chr2:287604 (GRCh38)
Gene constraint: LOEUF 1.297 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 71.41 · 5 PDB

Full ALKAL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALKAL2 p.Ala18Thr Uncertain significance ★ ⚠ same type
ALKAL2 p.Ala19Val Uncertain significance ★ ⚠ same type
ALKAL2 p.Ala26Pro Uncertain significance ★ ⚠ same type
ALKAL2 p.Arg140Trp Uncertain significance ★ ⚠ same type
ALKAL2 p.Arg23Pro Uncertain significance ★ ⚠ same type
ALKAL2 p.Arg29Gln Uncertain significance ★ ⚠ same type
ALKAL2 p.Arg2Cys Uncertain significance ★ ⚠ same type
ALKAL2 p.Arg39Trp 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/alkal2-p-pro78ser (accessed [today's date]).

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