Is GALM p.Phe222= (c.666C>T) pathogenic?

GALM p.Phe222= (c.666C>T) is classified Likely benign in GALM (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). Ultra-rare (popmax 0.0187%, afr).

How common is GALM p.Phe222= (c.666C>T) in the general population?

GALM p.Phe222= (c.666C>T) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

GALM p.Phe222=

c.666C>T · rs757065320 · VCV2894502

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP -4.4
Overall
CADD	6.695	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% African / African-American · 14/74,890 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.00118% 19/1,613,386 alleles · ultra-rare exomes 8/1,461,268 · genomes 11/152,118 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,349
Admixed American	0.00667%	14,991
European (non-Finnish)	8.48e-05%	1,179,618

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: GALM
Protein: p.Phe222=
Coding: c.666C>T
MANE Select: NM_138801
dbSNP: rs757065320
Type: single nucleotide variant
Location: chr2:38729587 (GRCh38)
Gene constraint: LOEUF 1.421 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.83 · 2 PDB
Residue 222: a UniProt-annotated variant site (in galac4; loss of protein accumulation)

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

Similar variants

GALM p.Arg131Cys Uncertain significance ★★ ⚠ same type
GALM p.Gly155Arg Uncertain significance ★★ ⚠ same type
GALM p.His333Arg Uncertain significance ★★ ⚠ same type
GALM p.Val8Met Uncertain significance ★★ ⚠ same type
GALM c.191-100G>T Benign ★★ same type
GALM c.191-128T>C Benign ★★ same type
GALM c.191-32T>A Benign ★★ same type
GALM c.553-49T>C Benign ★★ 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/galm-p-phe222 (accessed [today's date]).

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