Is MEGF8 p.Pro110Thr (c.328C>A) pathogenic?

MEGF8 p.Pro110Thr (c.328C>A) is classified Uncertain significance in MEGF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely benign (0.0969); Rare (popmax 0.112%, afr); Associated with MEGF8-related Carpenter syndrome.

What condition is associated with MEGF8 p.Pro110Thr (c.328C>A)?

MEGF8 p.Pro110Thr (c.328C>A) is associated with MEGF8-related Carpenter syndrome (ClinVar).

How common is MEGF8 p.Pro110Thr (c.328C>A) in the general population?

MEGF8 p.Pro110Thr (c.328C>A) is rare (popmax 0.112%, afr) (gnomAD).

What do computational predictors say about MEGF8 p.Pro110Thr (c.328C>A)?

AlphaMissense predicts likely benign (score 0.0969) — an in-silico prediction, not a clinical call.

MEGF8 p.Pro110Thr

c.328C>A · rs183986572 · VCV2427936

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0969 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.112%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

MEGF8-related Carpenter syndrome

Computational evidence

Protein change
AlphaMissense	0.0969	likely benign
REVEL	0.098	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.1	phastCons 0.56
Regional constraint	o/e 0.84	unconstrained · MANE · 51 kb · p 7.6e-23 · regional, not allelic
Overall
CADD	18.22	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.112% African / African-American · 84/75,050 alleles

Filtering AF 0.0926% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0855%

Overall 0.00564% 91/1,613,928 alleles · rare exomes 33/1,461,598 · genomes 58/152,330 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.112%	893
Admixed American	0.005%	20,005
Remaining individualsnot grpmax-eligible	0.0048%	20,827
European (non-Finnish)	8.48e-05%	1,179,860

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: MEGF8
Protein: p.Pro110Thr
Coding: c.328C>A
MANE Select: NM_001271938
dbSNP: rs183986572
Type: single nucleotide variant
Location: chr19:42333745 (GRCh38)
Gene constraint: LOEUF 0.696 · pLI <0.01 (gnomAD)
Residue 110: the cub 1 domain

Full MEGF8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

MEGF8-related Carpenter syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MEGF8 p.Arg419Ter Pathogenic/Likely pathogenic ★★ same condition
MEGF8 p.Arg991Ter Pathogenic/Likely pathogenic ★★ same condition
MEGF8 p.Ala1472Val Uncertain significance ★★ ⚠ same condition
MEGF8 p.Ala1572Thr Uncertain significance ★★ ⚠ same condition
MEGF8 p.Ala176Gly Uncertain significance ★★ ⚠ same condition
MEGF8 p.Ala1791Ser Uncertain significance ★★ same condition
MEGF8 p.Ala2104Ser Uncertain significance ★★ ⚠ same condition
MEGF8 p.Ala2349Gly Uncertain significance ★★ same condition

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/megf8-p-pro110thr (accessed [today's date]).

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