Is HM13 p.Pro25Ser (c.73C>T) pathogenic?

HM13 p.Pro25Ser (c.73C>T) is classified Uncertain significance in HM13 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-01). AlphaMissense: likely benign (0.1111); Very rare (popmax 0.00401%, afr).

How common is HM13 p.Pro25Ser (c.73C>T) in the general population?

HM13 p.Pro25Ser (c.73C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about HM13 p.Pro25Ser (c.73C>T)?

AlphaMissense predicts likely benign (score 0.1111) — an in-silico prediction, not a clinical call.

HM13 p.Pro25Ser

c.73C>T · rs1223624028 · VCV2321931

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1111 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1111	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -7.67	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 3.8	GERP 2.7, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 35 kb · p 0.00018 · regional, not allelic
Overall
CADD	21.0	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 0.00401% African / African-American · 3/74,724 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000189% 3/1,589,218 alleles · very rare exomes 3/1,436,878 · genomes 0/152,340 · joint denominator

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: HM13
Protein: p.Pro25Ser
Coding: c.73C>T
MANE Select: NM_178581
dbSNP: rs1223624028
Type: single nucleotide variant
Location: chr20:31514624 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 83.01
Residue 25: the 'disordered' region

Full HM13 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HM13 p.Ala350Val Uncertain significance ★ same type
HM13 p.Ala393Thr Uncertain significance ★ same type
HM13 p.Ala58Ser Uncertain significance ★ ⚠ same type
HM13 p.Ala75Thr Uncertain significance ★ ⚠ same type
HM13 p.Arg136Gln Uncertain significance ★ ⚠ same type
HM13 p.Arg179Lys Uncertain significance ★ ⚠ same type
HM13 p.Arg385Cys Uncertain significance ★ same type
HM13 p.Arg387His 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/hm13-p-pro25ser (accessed [today's date]).

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