Is CALHM5 p.Arg32Ser (c.94C>A) pathogenic?

CALHM5 p.Arg32Ser (c.94C>A) is classified Uncertain significance in CALHM5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: ambiguous (0.4265); Very rare (popmax 0.0011%, sas).

How common is CALHM5 p.Arg32Ser (c.94C>A) in the general population?

CALHM5 p.Arg32Ser (c.94C>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CALHM5 p.Arg32Ser (c.94C>A)?

AlphaMissense predicts ambiguous (score 0.4265) — an in-silico prediction, not a clinical call.

CALHM5 p.Arg32Ser

c.94C>A · VCV4647818

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4265 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4265	ambiguous
REVEL	0.239	benign-leaning
SaProt	LLR -9.62	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.47 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP 0.99, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 4,289 bp · p 0.81 · regional, not allelic
Overall
CADD	24.9	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 0.0011% South Asian · 1/91,080 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,613,906 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,080
European (non-Finnish)	0.000593%	168,570

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: CALHM5
Protein: p.Arg32Ser
Coding: c.94C>A
MANE Select: NM_153711
Type: single nucleotide variant
Location: chr6:116511790 (GRCh38)
Gene constraint: LOEUF 1.13 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.42 · 3 PDB
Residue 32: a binding site; an α-helix

Full CALHM5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CALHM5 p.Ala177Val Uncertain significance ★ ⚠ same type
CALHM5 p.Ala190Val Uncertain significance ★ ⚠ same type
CALHM5 p.Arg202Cys Uncertain significance ★ ⚠ same type
CALHM5 p.Arg202His Uncertain significance ★ ⚠ same type
CALHM5 p.Arg204Gln Uncertain significance ★ ⚠ same type
CALHM5 p.Arg90Ser Uncertain significance ★ ⚠ same type
CALHM5 p.Asn121Ser Uncertain significance ★ ⚠ same type
CALHM5 p.Asn13Ile 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/calhm5-p-arg32ser (accessed [today's date]).

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