Is SGMS2 p.Phe239Leu (c.715T>C) pathogenic?

SGMS2 p.Phe239Leu (c.715T>C) is classified Benign/Likely benign in SGMS2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-13). AlphaMissense: likely pathogenic (0.9796); Very rare (popmax 0.000424%, nfe).

How common is SGMS2 p.Phe239Leu (c.715T>C) in the general population?

SGMS2 p.Phe239Leu (c.715T>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about SGMS2 p.Phe239Leu (c.715T>C)?

AlphaMissense predicts likely pathogenic (score 0.9796) — an in-silico prediction, not a clinical call.

SGMS2 p.Phe239Leu

c.715T>C · VCV3683223

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9796 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9796	likely pathogenic
REVEL	0.598	indeterminate
SaProt	LLR -10.89	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.8	GERP 2.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 15 kb · p 0.0049 · regional, not allelic
Overall
CADD	27.5	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 0.000424% European (non-Finnish) · 5/1,179,838 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.0216% 349/1,613,848 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.528%	189
Remaining individualsnot grpmax-eligible	0.0096%	10,415
European (non-Finnish)grpmax	0.000424%	235,968

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SGMS2
Protein: p.Phe239Leu
Coding: c.715T>C
Type: single nucleotide variant
Location: chr4:107903374 (GRCh38)

Full SGMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/sgms2-p-phe239leu (accessed [today's date]).

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